Chromatin Modifications & SWI/SNF

Chromatin definition

Complex of DNA and proteins forming chromosomes

Nucleosome definition

146bp DNA wrapped around histone octamer

Histone octamer composition

H2A H2B H3 H4 (two copies each)

Histone tail function

Flexible regions subject to chemical modification

Globular histone domain

Structured core holding DNA contact

Post-translational modification purpose

Regulates gene expression by altering chromatin

Three enzyme categories

Writers erasers readers

Writers definition

Add chemical marks to histone tails

Erasers definition

Remove chemical marks

Readers definition

Recognise and bind existing marks

HAT stands for

Histone Acetyl Transferase

HAT function

Adds acetyl groups to lysine residues on histone tails

Histone acetylation effect

Neutralises positive charge loosening DNA binding

Chromatin opening via acetylation

Promotes transcriptionally active chromatin

Bromodomain function

Protein module recognising acetyl-lysine

Bdf1 example

Bromodomain protein binding acetyl-H4 to recruit TFIID

TAF1 bromodomain role

TAF subunit recognising acetylated histones

Acetylation and transcription

HATs coactivate by opening chromatin and recruiting machinery

HDAC stands for

Histone Deacetylase

HDAC function

Removes acetyl groups causing transcriptional repression

Four HDAC classes

Class I class II class IV zinc dependent and class III sirtuins

Sirtuins cofactor requirement

NAD dependent activity

HDAC complex behaviour

Often function as multisubunit repressors

SIN3 corepressor complex

Highly conserved HDAC-containing repression complex

NuRD complex full name

Nucleosome Remodeling and Deacetylase complex

NuRD dual function

ATP-dependent remodelling + deacetylation

NuRD biological role

Normal differentiation + tumourigenesis regulation

NuRD cancer relevance

Oncogenic TFs recruit NuRD to silence tumour suppressors

Histone methylation site

Mainly lysines and some arginines

HKMT stands for

Histone Lysine Methyl Transferase

SET domain function

Catalytic domain found in many HKMT enzymes

Histone methylation degrees

Mono di or tri methylation

Charge effect of methylation

None — does not neutralise lysine

Methylation regulatory outcome

Context-dependent activation or repression

Repressive methyl marks

H3K9 and H3K27 trimethylation

Activating methyl marks

H3K4 and H3K36 methylation

Demethylase role

Enzymes that remove methyl marks making methylation reversible

Reader for methyl marks

Chromodomain proteins and other modules

Chromodomain definition

Protein module binding methylated histones

ATP-dependent remodeling definition

Complexes that use ATP to reposition nucleosomes

Snf2 ATPase

Conserved catalytic core for remodelers

Remodelling families

Four major SF2 subfamilies

Remodelling reactions list

Sliding unwrapping eviction spacing histone variant exchange

Histone variant exchange example

Swr family swaps canonical H2A for variant H2A.Z

ATP hydrolysis purpose

Provides mechanical force to move DNA relative to histones

SWI/SNF discovery

First ATP-dependent remodeling complex identified in yeast

SWI/SNF catalytic subunit

Snf2/Swi2 in yeast

SWI/SNF ATP-consuming rate

Hydrolyses ~1000 ATP/min in presence of DNA/nucleosomes

SWI/SNF mechanism

Binds DNA and translocates like motor generating torsion

Nucleosome disruption result

Nucleosome repositioned or loosened to expose DNA

SWI/SNF function role

Facilitates TF binding and activation

HAT–SWI/SNF cooperation

HATs and SWI/SNF often act at same promoters

Bromodomain presence

Snf2 contains bromodomain aiding nucleosome targeting

Human SWI/SNF name

mSWI/SNF complexes

Human mSWI/SNF subtypes

cBAF PBAF ncBAF

Catalytic human paralogues

SMARCA4 (BRG1) and SMARCA2 (BRM)

Complex composition

Shared core subunits plus subtype-specific ones

Biological roles of SWI/SNF

Gene expression control differentiation and DNA repair

SWI/SNF mutation prevalence

Mutated in about 25% of all human cancers

SWI/SNF mutation types

Nonsense frameshift deletions implying loss of function

Diseases linked

Neurodevelopmental syndromes like Coffin-Siris and Nicolaides-Baraitser

Cancer examples linked

Rhabdoid tumours and gynecologic cancers

Tumour suppressor hypothesis

SWI/SNF loss leads to reduced TF access promoting cancer

Therapeutic opportunity

Mutated SWI/SNF cancers create vulnerabilities for targeting

Chromatin repression via structure

Nucleosomes block activator binding repressing genes by default

Active vs repressed landscape

Open euchromatin acetylated vs closed heterochromatin hypoacetylated

Remodeler recruitment

Often mediated by activators binding enhancers/promoters