Chromatin variant

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A chromatin variant corresponds to a section of the genome that differs in chromatin states across cell types/states within an individual (intra-individual) or between individuals for a given cell type/state (inter-individual). Chromatin variants distinguish DNA sequences that differ in their function in one cell type/state versus another. Chromatin variants are found across the genome, inclusive of repetitive and non-repetitive DNA sequence. [1] Chromatin variants range in sizes. The smallest chromatin variants cover a few hundred DNA base pairs, such as seen at promoters, enhancers or insulators. [2] [3] [4] [5] [6] The largest chromatin variants capture a few thousand DNA base pairs, such as seen at Large Organized Chromatin Lysine domains (LOCKs) [7] [8] [9] [10] and Clusters Of Cis-Regulatory Elements (COREs), such as super-enhancer. [11] [12]

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">Chromosome conformation capture</span>

Chromosome conformation capture techniques are a set of molecular biology methods used to analyze the spatial organization of chromatin in a cell. These methods quantify the number of interactions between genomic loci that are nearby in 3-D space, but may be separated by many nucleotides in the linear genome. Such interactions may result from biological functions, such as promoter-enhancer interactions, or from random polymer looping, where undirected physical motion of chromatin causes loci to collide. Interaction frequencies may be analyzed directly, or they may be converted to distances and used to reconstruct 3-D structures.

<span class="mw-page-title-main">Topologically associating domain</span> Self-interacting genomic region

A topologically associating domain (TAD) is a self-interacting genomic region, meaning that DNA sequences within a TAD physically interact with each other more frequently than with sequences outside the TAD. The median size of a TAD in mouse cells is 880 kb, and they have similar sizes in non-mammalian species. Boundaries at both side of these domains are conserved between different mammalian cell types and even across species and are highly enriched with CCCTC-binding factor (CTCF) and cohesin. In addition, some types of genes appear near TAD boundaries more often than would be expected by chance.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.

H2BK5ac is an epigenetic modification to the DNA packaging protein Histone H2B. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H2B protein. H2BK5ac is involved in maintaining stem cells and colon cancer.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H3K23ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 23rd lysine residue of the histone H3 protein.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K9ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 9th lysine residue of the histone H3 protein.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

References

  1. ↑ Grillo, Giacomo; Lupien, Mathieu (June 2022). "Cancer-associated chromatin variants uncover the oncogenic role of transposable elements". Current Opinion in Genetics & Development. 74: 101911. doi:10.1016/j.gde.2022.101911. ISSN   1879-0380. PMID   35487182.
  2. ↑ Ernst J, Kellis M (August 2010). "Discovery and characterization of chromatin states for systematic annotation of the human genome". Nature Biotechnology. 28 (8): 817–25. doi:10.1038/nbt.1662. PMC   2919626 . PMID   20657582.
  3. ↑ Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, et al. (March 2008). "FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription". Cell. 132 (6): 958–70. doi:10.1016/j.cell.2008.01.018. PMC   2323438 . PMID   18358809.
  4. ↑ Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, et al. (March 2007). "Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome". Nature Genetics. 39 (3): 311–8. doi:10.1038/ng1966. PMID   17277777. S2CID   1595885.
  5. ↑ Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, et al. (May 2009). "Histone modifications at human enhancers reflect global cell-type-specific gene expression". Nature. 459 (7243): 108–12. Bibcode:2009Natur.459..108H. doi:10.1038/nature07829. PMC   2910248 . PMID   19295514.
  6. ↑ Hoffman, Michael M.; Buske, Orion J.; Wang, Jie; Weng, Zhiping; Bilmes, Jeff A.; Noble, William Stafford (May 2012). "Unsupervised pattern discovery in human chromatin structure through genomic segmentation". Nature Methods. 9 (5): 473–476. doi:10.1038/nmeth.1937. ISSN   1548-7105. PMC   3340533 . PMID   22426492.
  7. ↑ Deblois G, Tonekaboni SA, Grillo G, Martinez C, Kao YI, Tai F, et al. (September 2020). "Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer". Cancer Discovery. 10 (9): 1312–1329. doi: 10.1158/2159-8290.CD-19-1493 . PMID   32546577.
  8. ↑ Timp W, Feinberg AP (July 2013). "Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host". Nature Reviews. Cancer. 13 (7): 497–510. doi:10.1038/nrc3486. PMC   4636434 . PMID   23760024.
  9. ↑ McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, et al. (March 2017). "Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis". Nature Genetics. 49 (3): 367–376. doi:10.1038/ng.3753. PMC   5695682 . PMID   28092686.
  10. ↑ Madani Tonekaboni SA, Haibe-Kains B, Lupien M (January 2021). "Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations". Nature Communications. 12 (1): 499. Bibcode:2021NatCo..12..499M. doi:10.1038/s41467-020-20830-9. PMC   7820432 . PMID   33479238.
  11. ↑ Madani Tonekaboni SA, Mazrooei P, Kofia V, Haibe-Kains B, Lupien M (October 2019). "Identifying clusters of cis-regulatory elements underpinning TAD structures and lineage-specific regulatory networks". Genome Research. 29 (10): 1733–1743. doi:10.1101/gr.248658.119. PMC   6771399 . PMID   31533978.
  12. ↑ Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. (November 2013). "Super-enhancers in the control of cell identity and disease". Cell. 155 (4): 934–47. doi:10.1016/j.cell.2013.09.053. PMC   3841062 . PMID   24119843.
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