Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of
these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the
principles of the human transcriptional regulatory network, we determined the genomic binding information of
119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of
transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations.
In particular, there are significant differences in the binding proximal and distal to genes. We organized all the
transcription factor binding into a hierarchy and integrated it with other genomic information (for example,
microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for
instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate
targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched
network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components
are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the
two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome
sequences and understanding basic principles of human biology and disease.
Direct Lineage Reprogramming: Novel Factors involved in Lineage ReprogrammingAhmed Madni
Direct linage reprogramming has got a major focus in biomedical field. The production of specific functional cell type from totally different cell lineage is called lineage reprogramming. In other words, it is induction of functional cell type from another linage without passing through intermediate stage of pluripotent.
A Network View on Parkinson’s Disease Elsevier webinar 15 jan 2015Ann-Marie Roche
Professor D.Bonchev shows an in-depth look at how a systems biology approach was used to identify some of the critical aspects Parkinson's disease: molecular players, drug targets, and underlying biological processes.
Direct Lineage Reprogramming: Novel Factors involved in Lineage ReprogrammingAhmed Madni
Direct linage reprogramming has got a major focus in biomedical field. The production of specific functional cell type from totally different cell lineage is called lineage reprogramming. In other words, it is induction of functional cell type from another linage without passing through intermediate stage of pluripotent.
A Network View on Parkinson’s Disease Elsevier webinar 15 jan 2015Ann-Marie Roche
Professor D.Bonchev shows an in-depth look at how a systems biology approach was used to identify some of the critical aspects Parkinson's disease: molecular players, drug targets, and underlying biological processes.
Graduate level educational lectures on innate and adaptive immune signaling mechanisms in two parts. Part 1 focuses on Antigen Receptor Signaling with focus on TCR singaling & the Immunological Synapse. Part 2 focuses on Cytokine Receptor, Notch and Innate Immunoreceptor Signaling as well as Regulation of signal dynamics. This material is taught as part of Immunobiology (BIOM514) at the University of New Mexico School of Medicine.
A functional and evolutionary perspective on transcription factor binding in ...Klaas Vandepoele
A functional and evolutionary perspective on transcription factor binding in Arabidopsis thaliana
Klaas Vandepoele
Comparative & Integrative Genomics group
Department of Plant Biotechnology and Bioinformatics, Ghent University
Department of Plant Systems Biology, VIB - Belgium
COMPETENCY 3Integrate credible and relevant sources into coursewLynellBull52
COMPETENCY 3
Integrate credible and relevant sources into coursework to enhance clarity and support claims.
CRITERION
Reflect on how credibility and relevance of a chosen resource were determined.
Your result: Non-Performance
Distinguished
Reflects on how credibility and relevance of a chosen resource were determined. Notes how specific aspects of the assessment were used to determine relevance.
Proficient
Reflects on how credibility and relevance of a chosen resource were determined.
Basic
Explains the concepts of credibility and relevance in general terms, but does not specifically address how this was used to determine if the specific resource was credible and relevant.
Non-Performance
Does not explain the concepts of credibility and relevance in general terms.
Faculty Comments:
I did not see a discussion of source credibility/relevance. For this assignment you were are also required to locate an article in the library about time organizing strategies (outlined in Part I). Then, you were asked in Part II to reflect on how you determined the credibility and relevance of your chosen library resource to support your task prioritization.
ONCOLOGY LETTERS 19: 595-605, 2020
Abstract. Numerous types of molecular mechanisms mediate
the development of cancer. Non-coding RNAs (ncRNAs) are
being increasingly recognized to play important role in medi-
ating the development of diseases, including cancer. Long
non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are
the two most widely studied ncRNAs. Thus far, lncRNAs are
known to have biological roles through a variety of mecha-
nisms, including genetic imprinting, chromatin remodeling,
cell cycle control, splicing regulation, mRNA decay and
translational regulation, and miRNAs regulate gene expres-
sion through the degradation of mRNAs and lncRNAs.
Although ncRNAs account for a major proportion of the total
RNA, the mechanisms underlying the physiological or patho-
logical processes mediated by various types of ncRNAs, and
the specific interaction mechanisms between miRNAs and
lncRNAs in various physiological and pathological processes,
remain largely unknown. Thus, further research in this field
is required. In general, the interaction mechanisms between
miRNAs and lncRNAs in human cancer have become
important research topics, and the study thereof has led to
the recent development of related technologies. By providing
examples and descriptions, and performing chart analysis, the
present study aimed to review the interaction mechanisms and
research approaches for these two types of ncRNAs, as well
as their roles in the occurrence and development of cancer.
These details have far‑reaching significance for the utilization
of these molecules in the diagnosis and treatment of cancer.
Contents
1. Introduction
2. Interactions between lncRNAs and miRNAs
3. Methods of research in to lncRNAs and miRNAs
4. lncRNAs and miRNAs in cancer
5. Conclusion
1. Introduction
In 1993, Lee e ...
Graduate level educational lectures on innate and adaptive immune signaling mechanisms in two parts. Part 1 focuses on Antigen Receptor Signaling with focus on TCR singaling & the Immunological Synapse. Part 2 focuses on Cytokine Receptor, Notch and Innate Immunoreceptor Signaling as well as Regulation of signal dynamics. This material is taught as part of Immunobiology (BIOM514) at the University of New Mexico School of Medicine.
A functional and evolutionary perspective on transcription factor binding in ...Klaas Vandepoele
A functional and evolutionary perspective on transcription factor binding in Arabidopsis thaliana
Klaas Vandepoele
Comparative & Integrative Genomics group
Department of Plant Biotechnology and Bioinformatics, Ghent University
Department of Plant Systems Biology, VIB - Belgium
COMPETENCY 3Integrate credible and relevant sources into coursewLynellBull52
COMPETENCY 3
Integrate credible and relevant sources into coursework to enhance clarity and support claims.
CRITERION
Reflect on how credibility and relevance of a chosen resource were determined.
Your result: Non-Performance
Distinguished
Reflects on how credibility and relevance of a chosen resource were determined. Notes how specific aspects of the assessment were used to determine relevance.
Proficient
Reflects on how credibility and relevance of a chosen resource were determined.
Basic
Explains the concepts of credibility and relevance in general terms, but does not specifically address how this was used to determine if the specific resource was credible and relevant.
Non-Performance
Does not explain the concepts of credibility and relevance in general terms.
Faculty Comments:
I did not see a discussion of source credibility/relevance. For this assignment you were are also required to locate an article in the library about time organizing strategies (outlined in Part I). Then, you were asked in Part II to reflect on how you determined the credibility and relevance of your chosen library resource to support your task prioritization.
ONCOLOGY LETTERS 19: 595-605, 2020
Abstract. Numerous types of molecular mechanisms mediate
the development of cancer. Non-coding RNAs (ncRNAs) are
being increasingly recognized to play important role in medi-
ating the development of diseases, including cancer. Long
non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are
the two most widely studied ncRNAs. Thus far, lncRNAs are
known to have biological roles through a variety of mecha-
nisms, including genetic imprinting, chromatin remodeling,
cell cycle control, splicing regulation, mRNA decay and
translational regulation, and miRNAs regulate gene expres-
sion through the degradation of mRNAs and lncRNAs.
Although ncRNAs account for a major proportion of the total
RNA, the mechanisms underlying the physiological or patho-
logical processes mediated by various types of ncRNAs, and
the specific interaction mechanisms between miRNAs and
lncRNAs in various physiological and pathological processes,
remain largely unknown. Thus, further research in this field
is required. In general, the interaction mechanisms between
miRNAs and lncRNAs in human cancer have become
important research topics, and the study thereof has led to
the recent development of related technologies. By providing
examples and descriptions, and performing chart analysis, the
present study aimed to review the interaction mechanisms and
research approaches for these two types of ncRNAs, as well
as their roles in the occurrence and development of cancer.
These details have far‑reaching significance for the utilization
of these molecules in the diagnosis and treatment of cancer.
Contents
1. Introduction
2. Interactions between lncRNAs and miRNAs
3. Methods of research in to lncRNAs and miRNAs
4. lncRNAs and miRNAs in cancer
5. Conclusion
1. Introduction
In 1993, Lee e ...
Rules and impact of nonsense-mediated mRNA decay in human cancersFran Supek
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs. We also show that dosage compensation may sometimes mask the effects of NMD. Applying the NMD model identifies signatures of both positive and negative selection on NMD-triggering mutations in human tumors and provides a classification for tumor-suppressor genes.
Tzitzikosta message for the world heritage monuments exhibitionAnax Fotopoulos
MESSAGE BY THE PRESIDENT OF THE HELLENIC NATIONAL COMMISSION FOR UNESCO EKATERINI TZITZIKOSTA OPENING OF THE PHOTOGRAPHIC EXHIBITION OF THE UNESCO WORLD HERITAGE SITES.
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules. RET loss of function mutations are associated with the development of Hirschsprung's disease, while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia.
RET is an abbreviation for "rearranged during transfection", as the DNA sequence of this gene was originally found to be rearranged within a 3T3 fibroblast cell line following its transfection with DNA taken from human lymphoma cells. The human gene RET is localized to chromosome 10 (10q11.2) and contains 21 exons.
The natural alternative splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 amino acids in their C-terminal tail respectively. The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo as these are the most common isoforms in which RET occurs.
Common to each isoform is a domain structure. Each protein is divided into three domains: an N-terminal extracellular domain with four cadherin-like repeats and a cysteine-rich region, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase domain, which is split by an insertion of 27 amino acids. Within the cytoplasmic tyrosine kinase domain, there are 16 tyrosines (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform.
The extracellular domain of RET contains nine N-glycosylation sites. The fully glycosylated RET protein is reported to have a molecular weight of 170 kDa although it is not clear to which isoform this molecular weight relates.
From Smart Homes to Smart Cities: An approach based on Internet-of-ThingsAnax Fotopoulos
Several applications and services have been developed over the latest years for making houses smarter in terms of danger prevention, energy consumption, waste recycling, environmental monitoring and other life improvement implementations. Internet-of-Things (IoT) gave numerous possibilities decentralizing the control of smart homes. Numerous sensors and developed systems or services can all communicate via smart devices like smartphones. A continuously broaden interest arises from local and national authorities for the benefits of applying IoT strategies in whole cities. With main focus on energy and water consumption, cities can reduce significantly their costs and become environmentally and economically sustainable. In the transition from smart homes to smart cities serious challenges should be take into consideration including a human-centric approach and the beneficiary involvement of the citizens for local and national authorities. The design of an IoT strategy for smart cities is a multifaceted procedure which includes the study of economic, urban, demographic and geographical indicators. In this paper, empirical evidence from selected case studies are presented.
The social aspect of Smart Wearable Systems in the era of Internet-of-ThingsAnax Fotopoulos
Social networking (Web 2.0) changed the way of interaction and communication of humans-to-humans, companies-to-customers, universities-to-students and state-to-citizens. The movement from static web pages (Web 1.0) to social networking and the rapid growth of smart devices created a new need for more complex data-on-demand across multiple platforms and devices. Cloud computing, miniaturization of sensors and low energy wireless technologies offered adequate possibilities to measure and understand environmental, health, industrial and other indicators, delivered in smart devices or in the web. The skyrocketing proliferation of the bidirectional communication between sensors and smart devices created a new series of products bringing us to the era of Internet-of-Things (IoT). The ubiquitous computing (presumed as Web 3.0) states that computing will appear in any device and in any location. Smart Wearable Systems (SWS) constitute the latest effort of academia and industry to toward this direction, aiming to enhance the communication and the velocity between IoT applications, smart devices (smartphones, tablets & smart TVs) and social networks. In this paper an analysis over social aspects of SWS is performed. Recent reports show that IoT market will be bigger than the total market of smart devices and PCs combined, enlarging the overall interest.
Introduction to HMMER - A biosequence analysis tool with Hidden Markov Models Anax Fotopoulos
HMMER is used for searching sequence databases for homologs of protein sequences, and for making protein sequence alignments. It implements methods using probabilistic models called profile hidden Markov models (profile HMMs).
Compared to BLAST, FASTA, and other sequence alignment and database search tools based on older scoring methodology, HMMER aims to be significantly more accurate and more able to detect remote homologs because of the strength of its underlying mathematical models. In the past, this strength came at significant computational expense, but in the new HMMER3 project, HMMER is now essentially as fast as BLAST.
As part of this evolution in the HMMER software, we are committed to making the software available to as many scientists as possible. Earlier releases of HMMER were restricted to command line use. To make the software more accessible to the wide scientific community, we now provide servers that allow sequence searches to be performed interactively via the Web.
TIS prediction in human cDNAs with high accuracyAnax Fotopoulos
Correct identification of the Translation Initiation Start (TIS) in cDNA is an important issue for genome annotation. The aim of this work is to improve upon current methods and provide a performance guaranteed prediction.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Architecture of the human regulatory network derived from encode data
1. ARCHITECTURE OF THE HUMAN REGULATORY
NETWORK DERIVED FROM ENCODE DATA
Gerstein MB, Kundaje A, Hariharan M, Landt SG, Yan KK, Cheng C, Mu XJ, Khurana E, Rozowsky
J, Alexander R, Min R, Alves P, Abyzov A, Addleman N,Bhardwaj N, Boyle AP, Cayting P, Charos
A, Chen DZ, Cheng Y, Clarke D, Eastman C, Euskirchen G, Frietze S, Fu Y, Gertz J, Grubert
F, Harmanci A, Jain P,Kasowski M, Lacroute P, Leng J, Lian J, Monahan H, O'Geen H, Ouyang
Z, Partridge EC, Patacsil D, Pauli F, Raha D, Ramirez L, Reddy TE, Reed B, Shi M,Slifer T, Wang
J, Wu L, Yang X, Yip KY, Zilberman-Schapira G, Batzoglou S, Sidow A, Farnham PJ, Myers
RM, Weissman SM, Snyder M.
Paper Presentation | Physiology |M.Sc., ITMB UoA
Anaxagoras Fotopoulos – Thanos Papathanasiou | 2014
Nature, 489(7414):91-100, 2012
2. INTRODUCTION
▪ System-wide analyses of transcription-factor-binding patterns have been performed in
unicellular model organisms, such as Escherichia coli.
▪ For humans, systems-level analyses have been a challenge due to the size of the
transcription factor repertoire and genome.
▪ Large-scale data from the ENCODE project begin to enable such analyses
▪ An analysis of the genome-wide binding profiles of 119 transcription-related factors
derived from 450 distinct experiments is performed, for finding correlations and
multi-transcription factor motifs.
▪ The results are integrated with other genomic information to form a multi-level meta-
network in which different levels have distinct properties.
▪ Information obtained in this study will be crucial to interpreting variants in the many
personal genome sequences expected in the future and understanding basic
principles of human biology and disease.
3. ENCODE
ChIP-seq data sets for 119 TF
over five main cell lines
Peak Detection
TF
For every peak
find intensities of
overlapping peaks
of all other factors
Generation of
Cobinding maps
(e.g. GATA1)
vs
Negative Set
created by independently
shuffling the peak intensity
values in each row of
the co-binding map
RULEFIT ALGORITHM
{Combination of
factors are compared
to randomized co-
binding map}
Positive Set
Randomized co-binding map Randomized co-binding map
Relative Importance Coassociation score
Aggregate across all
focus-factor contexts
Importance
correlation
matrix
Maximal
Coassociation
matrix
Data & Methods Analysis
4. POL2-(4H8)
TAL1
GATA2
Relative Importance gives the overall importance of each
transcription factor in the model. It reflects the ‘size’ of the
biclusters to which a particular transcription factor belongs,
and it is related to the number of co-binding factors and the
fraction of peak locations involved.
For GATA1 context primary partners POL2,
TAL1 and GATA2, as well as local partners
MAX and JUN, have high RI scores.
Co-association scores measure the impact of the co-
dependency implicit in a particular pair on the model as a
whole, and they more directly probe the co-occupancy of
transcription factors in the focus factor context than does
the RI score.
CCNT2–HMGN3 Novel Pair
MYC–MAX–E2F6
Expected Pairings Many Genes that lie near
clusters of co-associated
factors are enriched for
specific biological functions.
For example
• Bicluster {E2F6–GATA1–
GATA2–TAL1} was enriched
for genes related to
myeloid differentiation
• Bicluster {E2F6–SP1–SP2–
FOS–IRF1} was involved in
DNA damage response
Distinct combinations
of factors regulate
specific types of
genes.
Example of GATA1 Relative Importance & Co-association scores
5. CORRELATIONS OF TRANSCRIPTION FACTORS {1/7}
WITH DISTAL EDGES
Downward
Pointing Edges
Upward
Pointing Edges
Distal edges have a
different degree
distribution than
proximal ones.
Transcription factors with low in-degree values in the proximal
network but high in-degree values in the distal one, indicating
that they are heavily regulated through enhancers
Top
Level
Middle
Level
Bottom
Level
6. CORRELATIONS OF TRANSCRIPTION FACTORS {2/7}
WITHIN THE PROXIMAL NETWORK
• Upper-level transcription factors tend to
have more targets than lower-level ones
(Less Shaded TF).
• In middle-level, TF concentrate many in-
degree & out-degree information
(bottleneck) between top and bottom
level.
Top
Level
Middle
Level
Bottom
Level
Downward
Pointing Edges
Upward
Pointing Edges
7. CORRELATIONS OF TRANSCRIPTION FACTORS {3/7}
WITH PROTEIN INTERACTIONS AND THE PHOSPHORYLOME
Top-level transcription factors
tend to have more partners in
the protein–interaction network
than do lower-level ones.
Kinases at the bottom tend not to
phosphorylate transcription factors
Kinases at the bottom tend to be
regulated by transcription factors
Phosphorylome is a proteome
(entire set) of phosphoproteins
8. CORRELATIONS OF TRANSCRIPTION FACTORS {4/7}
WITH ncRNAs
Highly connected
transcription factors
tend to regulate more
miRNAs and to be more
regulated by them.
Top-level and middle-level
transcription factors have the highest
total number of ncRNA targets.
enriched for miRNA –>TF edges
Balanced number of edges
enriched for TF –> miRNA edges
9. CORRELATIONS OF TRANSCRIPTION FACTORS {5/7}
WITH FAMILIES AND FUNCTIONAL CATEGORIES
• Transcription factors at the top of the hierarchy tend to have more general
functions, and those at the bottom tend to have more specific functions.
• TFSSs show a greater degree of tissue specificity and are more highly regulated
by miRNAs than the general and chromatin-related factors
Chromatin-related
factors are
enriched at the top
of the hierarchy
TF Sequence-
Specific (TFSSs) are
enriched in the
middle
10. CORRELATIONS OF TRANSCRIPTION FACTORS {6/7}
WITH GENE EXPRESSION
•Highly connected factors tend to be highly expressed
•Top and middle levels show a greater correlation.
•More ‘influential’ transcription factors tend to be better
connected and higher in the hierarchy.
•A model integrating the binding–expression relationships of
the highly connected transcription factors has the same
influence (in prediction) with the less connected ones (weak
binding–expression).
Top-Middle and Middle-Middle
transcription factor pairs influence
gene expression cooperatively
11. CORRELATIONS OF TRANSCRIPTION FACTORS {7/7}
WITH NETWORK DYNAMICS
Transcription factors change their binding patterns
among different cell types.
Targets of lower-level transcription factors tend to
change more between cell types, consistent with their
role in more specialized processes.
‘Rewiring score’ is negatively correlated
with hierarchy level
Binding
Set 1
Binding
Set 2
Common
binding
sites
Rewiring score quantifies
the difference between two
sets of binding targets of a
TF in two cell lines
(Gm12878 and K562)
12. ENRICHED NETWORK MOTIFS {1/4}
AUTO-REGULATOR MOTIFS
Network motifs are small connectivity patterns that carry out canonical functions
Motifs in broad template patterns, could be over- or under-represented relative to a random control
•Human Regulatory Network is
enriched with auto-regulators
•Auto-regulators tend to be
repressors, representing a well
known design principle for
maintaining steady state.
•Auto-regulators have more ncRNAs
as their targets
Auto regulator is a simple but important motif which is
commonly found in networks exhibiting multistability.
90 TF are Non-Auto-regulators
28 TF are Auto-regulators
13. ENRICHED NETWORK MOTIFS {2/4}
THREE TRANSCRIPTION FACTOR MOTIFS
•The most enriched motif of the Three-transcription-factor
motifs in the proximal network is the feed-forward loop (FFL).
•From the expression levels of the genes of the FFLs over many
tissues, many were positively correlated
•Enriched three-transcription-factor motifs contain an
additional regulation on top of that in a FFL. This creates a
mutual regulation between a pair of transcription factors,
instantiating a toggle-switch, which has essential role in the
determination of the cell
Enrichment
Depletion
14. ENRICHED NETWORK MOTIFS {3/4}
PPI-MIMs MOTIFS
•Co-regulating transcription factors are likely to interact
physically, indicating that they work together as a complex.
•The motif ranking second in enrichment consists of a distal
regulatory relationship, a promoter regulatory relationship, and
a protein–protein interaction. Consisting of a DNA loop, with an
interacting complex of transcription factors binding to the
promoter and enhancer simultaneously.
Possible Multiple-Input-Modules involving promoter and distal regulation and a Protein–Protein Interaction (PPI-MIMs)
15. ENRICHED NETWORK MOTIFS {4/4}
miRNA REGULATION MOTIFS
•The miRNAs are more likely to regulate a pair of physically
interacting factors.
•In order to avoid unwanted cross-talk, a miRNA tends to
shut down an entire functional unit (transcription factor
complex) rather than just a single component .
•miRNAs tend to target a pair of transcription factors
binding both proximally and distally. This suggests that
miRNA represses the expression of both promoter and
distal regulators to shut down a target completely.
16. ALLELIC BEHAVIOR IN A NETWORK FRAMEWORK
•The degree of allele-specific behaviour of each transcription factor can be
quantified by a statistic that we call ‘allelicity’.
•of the 4,798 allele-specific binding cases (Paternal or Maternal Targets) of a single
transcription factor, 57% showed coordinated allelic binding and expression.
•Increment of the degree of combinatorial regulation, cause a progressively
stronger relationship between expressed and regulated alleles.
•Small insertions and deletions in TF sequences cause more allelic behavior than
SNPs.
Examining relationships between sequence variation and transcription factor regulation
TF
Target
Pat/Mat
Every line denotes
allele specific binding
17. CONCLUSIONS
• Human transcription factors co-associate in a combinatorial
and context-specific fashion.
• Different combinations of factors bind near different
targets, and the binding of one factor often affects the
preferred binding partners of others.
• Transcription factors often show different co-association
patterns in gene-proximal and distal regions
• Different parts of the hierarchical transcription factor
network exhibit distinct properties.
• Number of motifs in which two genes co-regulated by a
factor are bridged by a protein–protein interaction or
regulating miRNA.
• Both transcription factors and Targets are under strong
evolutionary selection and exhibit stronger allele-specific
activity but are under weaker selection than non-allelic
ones.
18. Thank youNational & Kapodistrian
University of Athens
Department of Informatics
Technological Education
Institute of Athens
Department of
Biomedical Engineering
Biomedical Research
Foundation
Academy of Athens
Demokritos
National Center
for Scientific Research
Physiology
Information Technologies in Medicine and Biology