H3K4me1

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H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

Contents

Nomenclature

H3K4me1 indicates monomethylation of lysine 4 on histone H3 protein subunit: [1]

Abbr.Meaning
H3H3 family of histones
Kstandard abbreviation for lysine
4position of amino acid residue

(counting from N-terminus)

memethyl group
1number of methyl groups added

Lysine methylation

Methylation of lysine.svg

This diagram shows the progressive methylation of a lysine residue. The mono-methylation (second from left) denotes the methylation present in H3K4me1.

Understanding histone modifications

The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as histones. The complexes formed by the looping of the DNA are known as chromatin. The basic structural unit of chromatin is the nucleosome: this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino (N) terminal charged tails are the site of the post-translational modifications, such as the one seen in H3K4me1. [2] [3]

Mechanism and function of modification

H3K4me1 is enriched at active and primed enhancers. [4] Transcriptional enhancers control the cell-identity gene expression and are important in the cell identity. Enhancers are primed by histone H3K4 mono-/di-methyltransferase MLL4 and then are activated by histone H3K27 acetyltransferase p300. [5] H3K4me1 fine-tunes the enhancer activity and function rather than controls. [4] H3K4me1 is put down by KMT2C (MLL3) and KMT2D (MLL4) [6]

LSD1, and the related LSD2/KDM1B demethylate H3K4me1 and H3K4me2. [7]

Marks associated with active gene transcription like H3K4me1 and H3K9me1 have very short half-lives. [8]

H3K4me1 with MLL3/4 can also act at promoters and repress genes. [8]

Relationship with other modifications

H3K4me1 is a chromatin signature of enhancers, H3K4me2 is highest toward the 5′ end of transcribing genes and H3K4me3 is highly enriched at promoters and in poised genes. H3K27me3, H4K20me1 and H3K4me1 silence transcription in embryonic fibroblasts, macrophages, and human embryonic stem cells (ESCs). [7]

Enhancers that have two opposing marks like the active mark H3K4me1 and repressive mark H3K27me3 at the same time are called bivalent or poised. These bivalent enhancers convert and become enriched with H3K4me1 and acetylated H3K27 (H3K27ac) after differentiation. [8]

Epigenetic implications

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to complex, combinatorial transcriptional output. It is thought that a Histone code dictates the expression of genes by a complex interaction between the histones in a particular region. [9] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. [10] The purpose of the epigenomic study was to investigate epigenetic changes across the entire genome. This led to chromatin states which define genomic regions by grouping the interactions of different proteins and/or histone modifications together. Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of ChIP-sequencing revealed regions in the genome characterised by different banding. [11] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. [12] A look in to the data obtained led to the definition of chromatin states based on histone modifications. [13] Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions.

The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate a genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers. This additional level of annotation allows for a deeper understanding of cell specific gene regulation. [14]

Clinical significance

Suppression of the H3K4 mono- and di-demethylase LSD-1 might extend lifespan in various species. [15]

H3K4me allows binding of MDB and increased activity of DNMT1 which could give rise to CpG island methylator phenotype (CIMP). CIMP is a type of colorectal cancers caused by the inactivation of many tumor suppressor genes from epigenetic effects. [16]

Methods

The histone mark H3K4me1 can be detected in a variety of ways:

1. Chromatin Immunoprecipitation Sequencing (ChIP-sequencing) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated. It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region. [17]

2. Micrococcal Nuclease sequencing (MNase-seq) is used to investigate regions that are bound by well positioned nucleosomes. Use of the micrococcal nuclease enzyme is employed to identify nucleosome positioning. Well positioned nucleosomes are seen to have enrichment of sequences. [18]

3. Assay for transposase accessible chromatin sequencing (ATAC-seq) is used to look in to regions that are nucleosome free (open chromatin). It uses hyperactive Tn5 transposon to highlight nucleosome localisation. [19] [20] [21]

See also

Related Research Articles

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

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.

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.

H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria.

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.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th 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.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R17me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 17th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R2me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 2nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3Y41P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 41st tyrosine residue of the histone H3 protein.

References

  1. ↑ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. Elsevier Science. pp. 21–38. ISBN   9780127999586.
  2. ↑ Ruthenburg AJ, Li H, Patel DJ, Allis CD (December 2007). "Multivalent engagement of chromatin modifications by linked binding modules". Nature Reviews. Molecular Cell Biology. 8 (12): 983–94. doi:10.1038/nrm2298. PMC   4690530 . PMID   18037899.
  3. ↑ Kouzarides T (February 2007). "Chromatin modifications and their function". Cell. 128 (4): 693–705. doi: 10.1016/j.cell.2007.02.005 . PMID   17320507.
  4. 1 2 Rada-Iglesias, Alvaro (2018). "Is H3K4me1 at enhancers correlative or causative?". Nature Genetics. 50 (1): 4–5. doi:10.1038/s41588-017-0018-3. PMID   29273804. S2CID   256821874.
  5. ↑ Wang, Chaochen; Lee, Ji-Eun; Lai, Binbin; MacFarlan, Todd S.; Xu, Shiliyang; Zhuang, Lenan; Liu, Chengyu; Peng, Weiqun; Ge, Kai (2016). "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition". Proceedings of the National Academy of Sciences. 113 (42): 11871–11876. doi: 10.1073/pnas.1606857113 . PMC   5081576 . PMID   27698142.
  6. ↑ Herz, H.-M.; Mohan, M.; Garruss, A. S.; Liang, K.; Takahashi, Y.-h.; Mickey, K.; Voets, O.; Verrijzer, C. P.; Shilatifard, A. (2012). "Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4". Genes & Development. 26 (23): 2604–2620. doi:10.1101/gad.201327.112. PMC   3521626 . PMID   23166019.
  7. 1 2 Hyun, Kwangbeom; Jeon, Jongcheol; Park, Kihyun; Kim, Jaehoon (2017). "Writing, erasing and reading histone lysine methylations". Experimental & Molecular Medicine. 49 (4): e324. doi:10.1038/emm.2017.11. PMC   6130214 . PMID   28450737.
  8. 1 2 3 Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-10-19). Epigenetic Gene Expression and Regulation. Academic Press. ISBN   9780128004715.
  9. ↑ Jenuwein T, Allis CD (August 2001). "Translating the histone code". Science. 293 (5532): 1074–80. CiteSeerX   10.1.1.453.900 . doi:10.1126/science.1063127. PMID   11498575.
  10. ↑ Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, et al. (The ENCODE Project Consortium) (June 2007). "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project". Nature. 447 (7146): 799–816. Bibcode:2007Natur.447..799B. doi:10.1038/nature05874. PMC   2212820 . PMID   17571346.
  11. ↑ Filion GJ, van Bemmel JG, Braunschweig U, Talhout W, Kind J, Ward LD, Brugman W, de Castro IJ, Kerkhoven RM, Bussemaker HJ, van Steensel B (October 2010). "Systematic protein location mapping reveals five principal chromatin types in Drosophila cells". Cell. 143 (2): 212–24. doi:10.1016/j.cell.2010.09.009. PMC   3119929 . PMID   20888037.
  12. ↑ Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, et al. (modENCODE Consortium) (December 2010). "Identification of functional elements and regulatory circuits by Drosophila modENCODE". Science. 330 (6012): 1787–97. Bibcode:2010Sci...330.1787R. doi:10.1126/science.1198374. PMC   3192495 . PMID   21177974.
  13. ↑ Kharchenko PV, Alekseyenko AA, Schwartz YB, Minoda A, Riddle NC, Ernst J, et al. (March 2011). "Comprehensive analysis of the chromatin landscape in Drosophila melanogaster". Nature. 471 (7339): 480–5. Bibcode:2011Natur.471..480K. doi:10.1038/nature09725. PMC   3109908 . PMID   21179089.
  14. ↑ Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, et al. (Roadmap Epigenomics Consortium) (February 2015). "Integrative analysis of 111 reference human epigenomes". Nature. 518 (7539): 317–30. Bibcode:2015Natur.518..317.. doi:10.1038/nature14248. PMC   4530010 . PMID   25693563.
  15. ↑ Sen, Payel; Shah, Parisha P.; Nativio, Raffaella; Berger, Shelley L. (2016). "Epigenetic Mechanisms of Longevity and Aging". Cell. 166 (4): 822–839. doi:10.1016/j.cell.2016.07.050. PMC   5821249 . PMID   27518561.
  16. ↑ Neidhart, Michel (2015-09-17). DNA Methylation and Complex Human Disease. Elsevier Science. p. 124. ISBN   978-0-12-420194-1.
  17. ↑ "Whole-Genome Chromatin IP Sequencing (ChIP-Seq)" (PDF). Illumina. Retrieved 23 October 2019.
  18. ↑ "MAINE-Seq/Mnase-Seq". illumina. Retrieved 23 October 2019.
  19. ↑ Buenrostro, Jason D.; Wu, Beijing; Chang, Howard Y.; Greenleaf, William J. (2015). "ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide". Current Protocols in Molecular Biology. 109: 21.29.1–21.29.9. doi:10.1002/0471142727.mb2129s109. ISBN   9780471142720. PMC   4374986 . PMID   25559105.
  20. ↑ Schep, Alicia N.; Buenrostro, Jason D.; Denny, Sarah K.; Schwartz, Katja; Sherlock, Gavin; Greenleaf, William J. (2015). "Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions". Genome Research. 25 (11): 1757–1770. doi:10.1101/gr.192294.115. ISSN   1088-9051. PMC   4617971 . PMID   26314830.
  21. ↑ Song, L.; Crawford, G. E. (2010). "DNase-seq: A High-Resolution Technique for Mapping Active Gene Regulatory Elements across the Genome from Mammalian Cells". Cold Spring Harbor Protocols. 2010 (2): pdb.prot5384. doi:10.1101/pdb.prot5384. ISSN   1559-6095. PMC   3627383 . PMID   20150147.
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