Epigenetik
Özet
Epigenetik, DNA dizisinde herhangi bir değişiklik olmaksızın gen ifadesinde meydana gelen ve hücre bölünmeleriyle kalıtılabilen değişiklikleri inceler. Bu bölüm, epigenetik düzenlemenin dört temel moleküler mekanizmasını, DNA metilasyonu ve demetilasyon dinamiği, histon modifikasyonları ve histon kodu, kodlamayan RNA'lar ile epitranskriptomik, kromatin yeniden düzenlenmesi ve üç boyutlu genom organizasyonu ayrıntılı biçimde ele almaktadır. Ardından bisülfit temelli dizileme (WGBS, RRBS), ChIP-seq, CUT&Tag, ATAC-seq, tek hücre yaklaşımları ve 3C/Hi-C teknikleri gibi temel araştırma yöntemleri tanıtılmaktadır. Gelişimsel süreçlerdeki epigenetik düzenleme, genomik damgalama (Prader-Willi ve Angelman sendromları) ile X kromozomu inaktivasyonu örnekleri üzerinden açıklanmakta; transgenerasyonel epigenetik kalıtım, intergenerasyonel kalıtımdan ayrılarak hayvan modelleri (Agouti, endokrin bozucu kimyasallar) ve insan epidemiyolojik verileri (Hollanda Açlık Kışı, Överkalix) ışığında eleştirel bir çerçevede tartışılmaktadır. Bölümün son kısmı, epigenetik düzensizliklerin kanser, nörogelişimsel ve nörodejeneratif bozukluklar ile metabolik hastalıklardaki rolüne; FDA onaylı epigenetik ilaçlara (DNMT, HDAC, EZH2 ve IDH inhibitörleri), klinik gelişim aşamasındaki yeni ajanlara, kombinasyon tedavilerine ve CRISPR-dCas9 tabanlı epigenom mühendisliğine ayrılmıştır. Epigenetik saatler, kişiselleştirilmiş tıpta biyobelirteç kullanımı ve alanın etik boyutu da değerlendirilmektedir.
Epigenetics examines heritable changes in gene expression that occur without any alteration in the underlying DNA sequence. This chapter provides a comprehensive treatment of the four core molecular mechanisms of epigenetic regulation: DNA methylation and demethylation dynamics, histone modifications and the histone code, non-coding RNAs together with the emerging field of epitranscriptomics, and chromatin remodelling and three-dimensional genome organisation. It then introduces the principal experimental approaches used in the field, including bisulfite-based sequencing (WGBS, RRBS), ChIP-seq, CUT&Tag, ATAC-seq, single-cell methods and 3C/Hi-C techniques. Epigenetic regulation during development is illustrated through genomic imprinting (Prader-Willi and Angelman syndromes) and X-chromosome inactivation. Transgenerational epigenetic inheritance is clearly distinguished from intergenerational effects and critically discussed in light of animal models (the Agouti mouse, endocrine-disrupting chemicals) and human epidemiological evidence (the Dutch Hunger Winter, Överkalix). The final sections address the role of epigenetic dysregulation in cancer, neurodevelopmental and neurodegenerative disorders, and metabolic disease, together with FDA-approved epigenetic drugs (DNMT, HDAC, EZH2 and IDH inhibitors), agents in clinical development, combination strategies, and CRISPR-dCas9-based epigenome engineering. Epigenetic clocks, biomarkers for personalised medicine, and the ethical dimensions of the field are also evaluated.
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