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선천성 알콜노출에 의한 후세대 영향 및 기전연구(이봄이)
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선천성 알콜노출에 의한 후세대 영향 및 기전연구(이봄이)

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선청성 알콜노출에 의한 후세대 영향 및 기전연구 …

선청성 알콜노출에 의한 후세대 영향 및 기전연구

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  • 핵내에서 dna와 유사한 정도의 양으로 많이 존재하는 히스톤 단백질은 아르기닌과 리신과 같이 전기적 양성을 띠는 아미노산의 비율이 높아 DNA골격 속의 인산기와 잘 결합할 수 있게 한다.
    특히 주목해야 할 것은 뉴클레오좀의 히스톤 팔량체 형성에 중요한 도메인 이외에 팔량체 구조 밖으로 자유롭게 뻗어 나온 아미노 말단 부위의 존재. 세포신호에 따른 암호가 새겨지는 기반으로 작용.
    즉, 핵심히스톤 단백질의 아미노 말단 부위의 아미노산 잔기들은 번역후 변형과정에 의해 조절되어 새로운 기능의 히스톤으로 탄생. 이것이 염색질 구조의 변화를 조절하는 주요 분자 스위치 역할을 가능하게 한다.
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    • 1. 알코올의 태아에 미치는 영향에 관한알코올의 태아에 미치는 영향에 관한 후성유전학적 기전 연구후성유전학적 기전 연구 유전학연구실유전학연구실 이봄이이봄이 Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics
    • 2. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics
    • 3. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics • Studies on changes in gene expression that are NOTNOT caused by changes in the sequence of DNA • The mitotically and meiotically heritable control of gene expression not related to DNA sequence during development Beyond the DNA Sequence!Beyond the DNA Sequence! EpigenomeEpigenome
    • 4. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics HeritableHeritable silencingsilencing Interaction of heritable silencingInteraction of heritable silencing •Small RNA mediated ControlSmall RNA mediated Control •Post-translation modificationPost-translation modification •CpG islandCpG island •Chromatin condensationChromatin condensation
    • 5. Gene “switched OFF”Gene “switched OFF” • Silent (condensed) chromatin • Methylated cytosines (red circles) • Deacetylated histones Gene “switched ON”Gene “switched ON” • Active (open) chromatin • unmethylated cytosines (white circles) • Acetylated histones
    • 6. • The most heavily studied mode of epigenetic regulation • By one of a variety of DNA methyltransferases (DNMTs) responsible for adding a methyl group to cytosine residues in cytosine/guanine- rich regions of DNA (called ‘CpG islands’) CpG islandsCpG islands • In and near approx. 40% of promoters of mammalian genes. • About 70% of human promoters have a high CpG content. • The “p” in CpG - phosphodiester bond between the cytosine and the guanine.
    • 7. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics • Classic Teratogen affecting to reduce growth factor levels - genetic, biochemical, cellular, and morphological • Interferes - DNA methylation - histone modification - noncoding RNA • Dosage and timing – inducing target organ developmental defect During PregnancyDuring Pregnancy
    • 8. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics • differences in timing and dosage underline this variability • preconception, preimplantation, and gastrulation • In Rat, placental mRNAs is altered after moderate drinking during pregnancy • Exposure to alcohol in the embryonic mouse can lead to structural and neurophysiologic changes. • Preconceptional effects mediated by paternal and maternal alcohol consumption Studies in the Animal ModelsStudies in the Animal Models
    • 9. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics • General assessment about fetal development • Limited human tissue specimen • Partially researched on tissue specific epigenetic study - Genome-wide methylation study via microarray • Rarely challenged to elucidate the relation of epigenetic changes within a family Studies In HumanStudies In Human
    • 10. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics
    • 11. 임신중 알코올 노출 임신부 및 태아 (n=100) vs 대조군 ( 임신중 알코올 비노출 임신부 및 태아 ) (n=100) 태아 알코올 증후군 및 알코올 대사 관련 대상유전자 선별 대상유전자 프로모터 부위 메틸화 양상 분석 모체 : 노출 시기별 채혈 태아 : 출생 시 태반과 제대혈 태아 발달 평가 임신중 태아 및 출생 후 발달 사항 자연유산 , 기형 , 조산 및 저체중증 기본정보수집 임신 초 , 중 , 말기 알코올 노출 기간 , 빈도 , 음주량 , 기타 ( 흡연 , 약물 ) 생체바이오마커 측정법 이용 임신중 알코올 노출 시기별 모체의 알코올 노출력 평가 생체바이오마커 측정법 이용 출생 시 태변에서 FAEEs 측정
    • 12. 임신전 알코올 노출 배우자 및 태아 (n=100) vs 대조군 ( 임신전 알코올 비노출 배우자 및 태아 ) (n=100) 태아 알코올 증후군 및 알코올 대사 관련 대상유전자 선별 대상유전자 프로모터 부위 메틸화 양상 분석 부체 : 노출 정도별 채혈 태아 : 출생 시 태반과 제대혈 태아 발달 평가 임신중 태아 및 출생 후 발달 사항 자연유산 , 기형 , 조산 및 저체중증 기본정보수집 알코올 노출 기간 , 임신전 금주기간 빈도 , 음주량 , 기타 ( 흡연 , 약물 ) 부체의 정액 검사 정자수 형태 운동성
    • 13. • Methylation pattern analysis - A genome-wide methylation analysis - micro array - Bisulfited genomic sequencing - Methylation-sensitive restriction enzyme - Gel electrophoresis analysis / fragment analysis • Target Gene expression level analysis : - Quantitative Real-time PCR • Candidate Target Gene : - Alcohol metabolism related genes ; ALDH2 (aldehyde dehydrogenase 2 family) , ADH1B (alcohol dehydrogenase 1B (class I) - Imprinting genes, Developmental related genes etc. ; H19 etc. - ADHD (attention-deficit hyperactivity disorder) related genes ; dopamine transporter gene, norepinephrine transporter gene - DNA Methylation related regulating genes ; DNMT (DNA methyltransferase), MECP2 (methyl CpG-binding protein 2) - Plasma homocysteine ; HERP (Homocysteine-induced ER protein) methylationunmethylation Restriction enzyme
    • 14. Cheil General Hospital & Women’s Healthcare CenterCheil General Hospital & Women’s Healthcare Center Laboratory of Medical GeneticsLaboratory of Medical Genetics