Types of histones, histone modifications and their effects

MICROBIOLOGY

1. TYPES OF HISTONES, HISTONE MODIFICATIONS AND THEIR EFFECTS ON STRUCTURE & FUNCTION OF CHROMATIN PRESENTED BY : Mousami Jaria St. George College of Management and Science MSc Microbiology Semester 2

2. HISTONE Histones are a family of basic protein that associate with DNA in nucleus and help condense it into chromatin . Nuclear DNA does not appear in free linear strands ;it is highly condensed and wrapped around histones in order to fit inside nucleus and take part in formation of chromosomes. Under the microscope, in its extended form chromatin looks like beads on string . The beads are called nucleosomes . Each nucleosome is made of DNA wrapped around 8 histone proteins that function like a spool and are called histone octamer .

3. Each histone octamer is composed of two copies each of the histone proteins H2A,H2B,H3&H4. The chain of nucleosome is then wrapped into a 30nm spiral called a solenoid , where additional H1 histone proteins are associated with each nucleosome to maintain chromosome structure. Histones are positively charged.

4. TYPES OF HISTONE There are two main classes of histones : Core histones Linker histones CORE HISTONES: Core histones include : H2A H2B H3 H4 Contains more lysine Contains more arginine

5. The core histones come together to form one nucleosome . The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer . LINKER HISTONES : Linker histones include: H1 H5 H1&H5 are include in higher order structures of chromatin H1 has about 220 residues H5 histones are individual proteins involved in the packaging of specific region of DNA. Highest lysine/ arginine ratio

6. FUNCTION OF HISTONES Histones primary functions are composed of DNA strands and impact chromatin regulation. Chromatin is a combination of DNA and protein which makes up the contents of a cell nucleus . Without histones the unwound DNA in the chromosomes would be very long Because DNA wraps around histones , they also play a important role in chromatin regulation and gene expression . Some histone protein function as spools for the thread like DNA to wrap around.

7. HISTONE MODIFICATION A histone modification is a covalent post transational modification (PTM) to histone proteins which includes: Methylation Phosphorylation Acetylation Ubiqitylation SUMOylation

8. ACETYLATION It is most widely studied histone modification. Acetylation adds a negative charge to lysine residues on the N-terminal histone tails that extend out from the nucleosome . These negative charges repel negatively charged DNA , which results in a relaxed chromatin structure. The open chromatin conformation allows transcription factor binding and significantly increases gene expression.

9. Histone acetylation is involved in cell cycle regulation , cell proliferation , apoptosis & may play a vital role in regulating many other cellular processes , including DNA replication & repair , neuronal repression. An imbalance in the equillibrium of histone acetylation is associated with tumorigenesis and cancer progression. Acetyl groups are added to lysine residues of histones H3, H4 by histone acetyltransferases (HAT0 & removed by deacetyllases (HDAC). Histone acetylation is largely targeted to promoter regions.

10. METHYLATION It is the transfer of one ,two or three methyl groups from S- adenosyl -L- methionine to lysine or arginine residues of histone proteins by histone methyltransferases (HMT). HMTs control or regulate DNA methylation through chromatin dependent transcriptional repression or activation It has its role in both activation and repression Arginines can be mono- or dimethylated whereas lysines can be mono-, di -, or trimethylated .

11. Methylation can result in activation or repression of expression: ACTIVATION (H3K4, H3K36, H3K79 ) Trimethylation of histone H3 at lysine 4 (H3K4) is a universal active mark for transcription. REPRESSION (H3K9, H3K27,H4K20 ) Dimethylation of histone H3 at lysine 9 (H3K9) and at lysine 27 (H3K27) are the universal signal for transcriptional silencing.

12. HISTONE METHYLATION

13. ROLE OF METHYLATION IN HETEROCHROMATIN FORMATION : Condensation assisted by recruitment of HMT , where HP1 (Heterochromatin protein 1) binds to H3K9-Me3 which methylates adjacent H3K9. Chromatin condensed untill a boundary element is reached and turned into heterochromatin. Methylation of histone tails longlasting compared to acetylation . Can be inherited by daughter cells , responsible for X-inactivation in female

14. PHOSPHORYLATION Histone phosphorylation stablishes interactions between other histone modifications and serves as a platform for effector proteins , which leads to many events. Phosphorylation of histone H3 at serine 10&28, and histone H2A o T120 are involved in chromatin compaction and the regulation of chromatin stucture & function during mitosis. These are important markers of cell cycle and cell growth that are conserved throughout eukaryotes .

15. Phosphorylation of H2AX at S139 serves as a recruiting point for DNA damge repair proteins. H2B phosphorylation facilitates apoptosis related chromatin condensation , DNA fragmentation and cell death .

16. SENSORS OF HISTONE PHOSPHORYLATION DURING INTERPHASE & MITOSIS