复旦大学：《表观遗传学》（英文版）Chromatin has important role in gene regulation

廳遗 Epigenetics Chromatin based gene control Chaoqun Wu School of Life Sciences, Fudan University 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 1 Epigenetics — Chromatin based gene control Chaoqun Wu School of Life Sciences, Fudan University

Part‖l Chromatin has important role in gene regulation 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 2 Part II. Chromatin has important role in gene regulation

Multiple levels of gene regulation inactive mRNA NUCLEUS CYTOSOL mRNA degradation 5 contro RNA DNA transcript mRNA mRNA transcriptional RNA RNA control processing transport translation protein control and control activity local ization control contro protein In nactive protein 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 3 Multiple levels of gene regulation

RNA polymerase transcribes genes How is this process regulated? How is specificity achieved? Key players transcriptional activator proteins bind to specific sites on dNA and turn on the expression of nearby genes Two adhesive surfaces one binds dna. the other interacts with and recruits RNa polymerase 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 4 RNA polymerase transcribes genes - How is this process regulated? How is specificity achieved? Key players – transcriptional activator proteins -bind to specific sites on DNA and turn on the expression of nearby genes. Two adhesive surfaces – one binds DNA, the other interacts with, and recruits RNA polymerase

Enzyme specificity Many enzymes are capable of acting on a common motif found in many different proteins-EXample -kinases General solution recruitment through specific protein protein interactions Regulated localization -locator proteins 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 5 Enzyme specificity – Many enzymes are capable of acting on a common motif found in many different proteins - Example - kinases General solution – recruitment through specific protein￾protein interactions. Regulated localization - locator proteins

How is transcription initiated in eukaryotes Inhibitors can bind blocking binding of other general transcription factors TFIID binds to TATA bOX (TFIID composed of TBP[TATA-binding TATA box ranscribed regio protein) and more than eight other IIDTAFs subunit[TAFs)) FllA prevents inhibitor binding TFIIB binds to D-A complex lID Pol Preformed complex RNa polymerase ll and TFllF bind TFIIE, TFIIH, and TFIlJ add to complex in that order now transcription can begin Pol ll 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 6 How is transcription initiated in eukaryotes TFIID binds to TATA box (TFIID composed of TBP{TATA-binding protein} and more than eight other subunit{TAFs}) Inhibitors can bind blocking binding of other general transcription factors TFIIA prevents inhibitor binding TFIIB binds to D-A complex Preformed complex RNA polymerase II and TFIIF bind TFIIE, TFIIH, and TFIIJ add to complex in that order now transcription can begin

Where does eukaryote transciption occur? Ac HAT MAMAC HDAC Ac AC unacetylated acetylated silent active Modifications act as code for the recognition of other factors/requlator factors 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 7 Where does eukaryote transciption occur? Modifications act as code for the recognition of other factors/ regulator factors

Eukaryotic transcription occurs in the context of chromatin Modification of chromatin is a common theme in modulation of eukaryotic gene regulation Histone modifications Acetylation of histone tail generally associated With active gene expression Unacetylated histone tails generally associated with gene silence o Methylation of histone tail may be associated with active or inactive genes Phosphorylation generally associated with active gene expression though currently unclear 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 8 Eukaryotic transcription occurs in the context of chromatin Modification of chromatin is a common theme in modulation of eukaryotic gene regulation Histone modifications ◆ Acetylation of histone tail generally associated with active gene expression ◆ Unacetylated histone tails generally associated with gene silence ◆ Methylation of histone tail may be associated with active or inactive genes ◆ Phosphorylation generally associated with active gene expression though currently unclear

Transcriptional regulation in the context of chromatin Activators These proteins bind to genes at sites known as enhancers Repressors and speed the rate These proteins bind of transcription Enhancer at sites known as silencers The basics of and thus slow transcription eukaryotic Activator gene regulation Activator Activator 110 RNA TATA box Coactivators Core promoter These“ adapter” molecules integrate signals from activators Basal transcription factors and perhaps repressors In response to injunctions from activators, these factors position RNA polymerase at the start of 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 9 Transcriptional regulation in the context of chromatin The basics of eukaryotic gene regulation

Enhancesome and a repressosome Enhanceosome Involves the cooperative BP is an acety lase assembly of a multiprotein complex containing several ATF-2 factors/activators These complexes recruit CBP Which activates transcription IR F37 CBP mediator B-interferon enhanceosome Repressosome Pol Il NFKB Involves a multiprotein complex containing severa HMGIY factors/repressors B These factors recruit Groucho M which blocks formation or function of the basal Ring transcription complex by Cal mediator Groucho interacting with TFIlE Groucho repressosome Pol Il Groucho may associate with deacety lase 2005-10-29 Chaoqun Wu, Fudan University

2005-10-29 Chaoqun Wu, Fudan University Chaoqun Wu, Fudan University 10 Enhancesome and a repressosome Enhanceosome Involves the cooperative assembly of a multiprotein complex containing several factors/activators These complexes recruit CBP which activates transcription β-interferon enhanceosome Repressosome Involves a multiprotein complex containing several factors/repessors These factors recruit Groucho which blocks formation or function of the basal transcription complex by interacting with TFIIE Groucho repressosome CBP is an acetylase Groucho may associate with deacetylase