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Hanna Yang, Chang Seob Kwon, Yoonjung Choi, Daeyoup Lee
Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5' promoter and 3' termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes...
August 5, 2016: Biochemical and Biophysical Research Communications
Karine Jacquet, Amélie Fradet-Turcotte, Nikita Avvakumov, Jean-Philippe Lambert, Céline Roques, Raj K Pandita, Eric Paquet, Pauline Herst, Anne-Claude Gingras, Tej K Pandita, Gaëlle Legube, Yannick Doyon, Daniel Durocher, Jacques Côté
The NuA4/TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here we identified MBTD1 as a stable subunit of the complex, and we reveal that, via a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double-strand breaks by homologous recombination. It was previously suggested that TIP60-dependent acetylation of H4 regulates binding of the non-homologous end joining factor 53BP1, which engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub...
May 5, 2016: Molecular Cell
Xingrao Ke, Bohan Xing, Baifeng Yu, Xing Yu, Amber Majnik, Susan Cohen, Robert Lane, Lisa Joss-Moore
Intrauterine growth restriction (IUGR) programs neurodevelopmental impairment and long-term neurological morbidities. Neurological morbidities in IUGR infants are correlated with changes hippocampal volume. We previously demonstrated that IUGR alters hippocampal cellular composition in both neonatal and juvenile rat pups in association with altered hippocampal gene expression and epigenetic determinants. PPARγ signaling is important for neurodevelopment as well as epigenetic integrity in the brain via the PPARγ-Setd8-H4K20me(1) axis and Wnt signaling...
November 2014: International Journal of Developmental Neuroscience
Ondrej Podlaha, Subhajyoti De, Mithat Gonen, Franziska Michor
Mechanisms that generate transcript diversity are of fundamental importance in eukaryotes. Although a large fraction of human protein-coding genes and lincRNAs produce more than one mRNA isoform each, the regulation of this phenomenon is still incompletely understood. Much progress has been made in deciphering the role of sequence-specific features as well as DNA-and RNA-binding proteins in alternative splicing. Recently, however, several experimental studies of individual genes have revealed a direct involvement of epigenetic factors in alternative splicing and transcription initiation...
June 2014: PLoS Computational Biology
Stine Jørgensen, Gunnar Schotta, Claus Storgaard Sørensen
Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction...
March 1, 2013: Nucleic Acids Research
Andrea J Hartlerode, Yinghua Guan, Anbazhagan Rajendran, Kiyoe Ura, Gunnar Schotta, Anyong Xie, Jagesh V Shah, Ralph Scully
Recruitment of 53BP1 to chromatin flanking double strand breaks (DSBs) requires γH2AX/MDC1/RNF8-dependent ubiquitination of chromatin and interaction of 53BP1 with histone H4 methylated on lysine 20 (H4K20me). Several histone methyltransferases have been implicated in 53BP1 recruitment, but their quantitative contributions to the 53BP1 response are unclear. We have developed a multi-photon laser (MPL) system to target DSBs to subfemtoliter nuclear volumes and used this to mathematically model DSB response kinetics of MDC1 and of 53BP1...
2012: PloS One
David B Beck, Hisanobu Oda, Steven S Shen, Danny Reinberg
Histone post-translational modifications impact many aspects of chromatin and nuclear function. Histone H4 Lys 20 methylation (H4K20me) has been implicated in regulating diverse processes ranging from the DNA damage response, mitotic condensation, and DNA replication to gene regulation. PR-Set7/Set8/KMT5a is the sole enzyme that catalyzes monomethylation of H4K20 (H4K20me1). It is required for maintenance of all levels of H4K20me, and, importantly, loss of PR-Set7 is catastrophic for the earliest stages of mouse embryonic development...
February 15, 2012: Genes & Development
Zhenfei Li, Fen Nie, Sheng Wang, Lin Li
Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 monomethylation (H4K20me-1) in transcriptional regulation remains unclear. Here, we show that Wnt3a specifically stimulates H4K20 monomethylation at the T cell factor (TCF)-binding element through the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with lymphoid enhancing factor-1 (LEF1)/TCF4 directly, and this interaction is regulated by Wnt3a...
February 22, 2011: Proceedings of the National Academy of Sciences of the United States of America
Stanley A Moore, Yurdagul Ferhatoglu, Yunhua Jia, Rami A Al-Jiab, Maxwell J Scott
We have determined the human male specific lethal 3 (hMSL3) chromo-barrel domain structure by x-ray crystallography to a resolution of 2.5 Å (r = 0.226, R(free) = 0.270). hMSL3 contains a canonical methyllysine binding pocket made up of residues Tyr-31, Phe-56, Trp-59, and Trp-63. A six-residue insertion between strands β(1) and β(2) of the hMSL3 chromo-barrel domain directs the side chain of Glu-21 into the methyllysine binding pocket where it hydrogen bonds to the NH group of a bound cyclohexylamino ethanesulfonate buffer molecule, likely mimicking interactions with a histone tail dimethyllysine residue...
December 24, 2010: Journal of Biological Chemistry
Lisa A Joss-Moore, Yan Wang, Michelle L Baack, Jianrong Yao, Andrew W Norris, Xing Yu, Christopher W Callaway, Robert A McKnight, Kurt H Albertine, Robert H Lane
Intrauterine growth restriction (IUGR) is associated with altered lung development in human and rat. The transcription factor PPARγ, is thought to contribute to lung development. PPARγ is activated by docosahexanoic acid (DHA). One contribution of PPARγ to lung development may be its direct regulation of chromatin modifying enzymes, such as Setd8. In this study, we hypothesized that IUGR would result in a gender-specific reduction in PPARγ, Setd8 and associated H4K20Me levels in the neonatal rat lung. Because DHA activates PPARγ, we also hypothesized that maternal DHA supplementation would normalize PPARγ, Setd8, and H4K20Me levels in the IUGR rat lung...
December 2010: Early Human Development
Yu Wang, Songtao Jia
Residue and degree-specific methylation of histone lysines along with other epigenetic modifications organizes chromatin into distinct domains and regulates almost every aspect of DNA metabolism. Identification of histone methyltransferases and demethylases, as well as proteins that recognize methylated lysines, has clarified the role of each methylation event in regulating different biological pathways. Methylation of histone H4 lysine 20 (H4K20me) plays critical roles in diverse cellular processes such as gene expression, cell cycle progression and DNA damage repair, with each of the three degrees of methylation (mono-, di- and tri-methylation) making a unique contribution...
July 1, 2009: Epigenetics: Official Journal of the DNA Methylation Society
Yu Wang, Bharat Reddy, James Thompson, Hengbin Wang, Ken-ichi Noma, John R Yates, Songtao Jia
Methylation of histone H4 lysine 20 (H4K20me) is essential for recruiting checkpoint proteins 53BP1/Crb2 to DNA lesions and subsequent activation of a DNA-damage checkpoint. In fission yeast, Set9 (spKMT5) catalyzes mono-, di-, and trimethylation of H4K20. However, the mechanisms that regulate Set9 function are poorly understood. Here, we identified a PWWP domain protein Pdp1 as a Set9-associated factor. Pdp1 binds to histones and is required for Set9 chromatin localization. Yeast cells without Pdp1 were deficient in all three states of H4K20me, sensitive to genotoxic treatments, and impaired in Crb2 recruitment...
February 27, 2009: Molecular Cell
Xingwu Lu, Sandeep N Wontakal, Alexander V Emelyanov, Patrick Morcillo, Alexander Y Konev, Dmitry V Fyodorov, Arthur I Skoultchi
We generated mutant alleles of Drosophila melanogaster in which expression of the linker histone H1 can be down-regulated over a wide range by RNAi. When the H1 protein level is reduced to approximately 20% of the level in wild-type larvae, lethality occurs in the late larval - pupal stages of development. Here we show that H1 has an important function in gene regulation within or near heterochromatin. It is a strong dominant suppressor of position effect variegation (PEV). Similar to other suppressors of PEV, H1 is simultaneously involved in both the repression of euchromatic genes brought to the vicinity of pericentric heterochromatin and the activation of heterochromatic genes that depend on their pericentric localization for maximal transcriptional activity...
February 15, 2009: Genes & Development
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