H3K4me3

H3K4me3 is an epigenetic chemical modification involved in the regulation of gene expression.[1] The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein. H3 is used to package DNA in eukaryotic cells (including human cells), and modifications to the histone alter the accessibility of genes for transcription. H3K4me3 is commonly associated with the activation of transcription of nearby genes. H3K4 trimethylation regulates gene expression through chromatin remodeling by the NURF complex.[2] In bivalent chromatin, H3K4me3 is co-localized with the repressive modification H3K27me3 to control gene regulation.[3] H3K4me3 also plays an important role in the genetic regulation of stem cell potency and lineage.[4]

Lysine methylation

The H3K4me3 modification is created by a lysine-specific histone methyltransferase (HMT) transferring three methyl groups to histone H3.[5] H3K4me3 is methylated by methyltransferase complexes containing a protein WDR5, which contains the WD40 repeat protein motif.[6] WDR5 associates specifically with dimethylated H3K4 and allows further methylation by methyltransferases, allowing for the creation and readout of the H3K4me3 modification.[7] WDR5 activity has been shown to be required for developmental genes, like the Hox genes, that are regulated by histone methylation.[6]

Epigenetic marker

H3K4me3 is a commonly used histone modification. H3K4me3 is one of the least abundant histone modifications; however, it is highly enriched at active promoters near transcription start sites (TSS) [8] and positively correlated with transcription. H3K4me3 is used as a histone code or histone mark in epigenetic studies (usually identified through chromatin immunoprecipitation) to identify active gene promoters.

H3K4me3 promotes gene activation through the action of the NURF complex, a protein complex that acts through the PHD finger protein motif to remodel chromatin.[2] This makes the DNA in the chromatin accessible for transcription factors, allowing the genes to be transcribed and expressed in the cell.

Role in stem cells and embryogenesis

Regulation of gene expression through H3K4me3 plays a significant role in stem cell fate determination and early embryo development. Pluripotent cells have distinctive patterns of methylation that can be identified through ChIP-seq, permitting the identification of pluripotent cells. This is important in the development of induced pluripotent stem cells, in which one of the indicators of successful pluripotency induction is through comparing the epigenetic pattern to that of embryonic stem cells.[9]

In embryonic cells, H3K4me3 is part of a system of bivalent chromatin, in which regions of DNA are simultaneously marked with activating and repressing histone methylations.[3] This is believed to allow for a flexible system of gene expression, in which genes are primarily repressed, but due to the presence of H3K4me3, may be expressed quickly as the cell progresses through development.[4] These regions tend to coincide with transcription factor genes expressed at low levels.[4] Some of these factors, such as the Hox genes, are essential for control development and cellular differentiation during embryogenesis.[2][4]

See also

References

  1. ↑ Sims RJ, Nishioka K, Reinberg D (November 2003). "Histone lysine methylation: a signature for chromatin function". Trends in Genetics. 19 (11): 629–39. doi:10.1016/j.tig.2003.09.007. PMID 14585615.
  2. 1 2 3 Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, Wu C, Allis CD (July 2006). "A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling". Nature. 442 (7098): 86–90. doi:10.1038/nature04815. PMID 16728976.
  3. 1 2 Vastenhouw NL, Schier AF (June 2012). "Bivalent histone modifications in early embryogenesis". Current Opinion in Cell Biology. 24 (3): 374–86. doi:10.1016/j.ceb.2012.03.009. PMC 3372573. PMID 22513113.
  4. 1 2 3 4 Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (April 2006). "A bivalent chromatin structure marks key developmental genes in embryonic stem cells". Cell. 125 (2): 315–26. doi:10.1016/j.cell.2006.02.041. PMID 16630819.
  5. ↑ Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD (December 2003). "Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains". Molecular Cell. 12 (6): 1591–8. doi:10.1016/s1097-2765(03)00479-9. PMID 14690610.
  6. 1 2 Wysocka J, Swigut T, Milne TA, Dou Y, Zhang X, Burlingame AL, Roeder RG, Brivanlou AH, Allis CD (June 2005). "WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development". Cell. 121 (6): 859–72. doi:10.1016/j.cell.2005.03.036. PMID 15960974.
  7. ↑ Ruthenburg AJ, Wang W, Graybosch DM, Li H, Allis CD, Patel DJ, Verdine GL (August 2006). "Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex". Nature Structural & Molecular Biology. 13 (8): 704–12. doi:10.1038/nsmb1119. PMC 4698793. PMID 16829959.
  8. ↑ Liang G, Lin JC, Wei V, Yoo C, Cheng JC, Nguyen CT, Weisenberger DJ, Egger G, Takai D, Gonzales FA, Jones PA (May 2004). "Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome". Proceedings of the National Academy of Sciences of the United States of America. 101 (19): 7357–62. doi:10.1073/pnas.0401866101. PMC 409923. PMID 15123803.
  9. ↑ Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RD (July 2007). "New cell lines from mouse epiblast share defining features with human embryonic stem cells". Nature. 448 (7150): 196–9. doi:10.1038/nature05972. PMID 17597760.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.