Elevated placental histone H3K4 methylation via upregulated histone methyltransferases SETD1A and SMYD3 in preeclampsia and its possible involvement in hypoxia-induced pathophysiological process

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

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Genetic Interactions of Histone Modification Machinery Set1 and PAF1C with the Recombination Complex Rec114-Mer2-Mei4 in the Formation of Meiotic DNA Double-Strand Breaks

International Journal of Molecular Sciences ◽

10.3390/ijms21082679 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2679

Author(s):

Ying Zhang ◽

Takuya Suzuki ◽

Ke Li ◽

Santosh K. Gothwal ◽

Miki Shinohara ◽

...

Keyword(s):

Histone Modification ◽

Genetic Interaction ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

H3k4 Methylation ◽

Yeast Saccharomyces Cerevisiae ◽

Strand Breaks ◽

Histone H3k4 ◽

Genomic Locations ◽

Chromosome Axis

Homologous recombination is essential for chromosome segregation during meiosis I. Meiotic recombination is initiated by the introduction of double-strand breaks (DSBs) at specific genomic locations called hotspots, which are catalyzed by Spo11 and its partners. DSB hotspots during meiosis are marked with Set1-mediated histone H3K4 methylation. The Spo11 partner complex, Rec114-Mer2-Mei4, essential for the DSB formation, localizes to the chromosome axes. For efficient DSB formation, a hotspot with histone H3K4 methylation on the chromatin loops is tethered to the chromosome axis through the H3K4 methylation reader protein, Spp1, on the axes, which interacts with Mer2. In this study, we found genetic interaction of mutants in a histone modification protein complex called PAF1C with the REC114 and MER2 in the DSB formation in budding yeast Saccharomyces cerevisiae. Namely, the paf1c mutations rtf1 and cdc73 showed synthetic defects in meiotic DSB formation only when combined with a wild-type-like tagged allele of either the REC114 or MER2. The synthetic defect of the tagged REC114 allele in the DSB formation was seen also with the set1, but not with spp1 deletion. These results suggest a novel role of histone modification machinery in DSB formation during meiosis, which is independent of Spp1-mediated loop-axis tethering.

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Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

10.1101/567917 ◽

2019 ◽

Cited By ~ 1

Author(s):

Christina N. Vallianatos ◽

Brynne Raines ◽

Robert S. Porter ◽

Katherine M. Bonefas ◽

Michael C. Wu ◽

...

Keyword(s):

Dendritic Spines ◽

Histone H3 ◽

Dendritic Morphology ◽

H3k4 Methylation ◽

Neuronal Structure ◽

Double Mutation ◽

Behavioral Traits ◽

Functional Interactions ◽

Histone H3k4 ◽

The Brain

AbstractHistone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

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H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development

10.1101/301986 ◽

2018 ◽

Author(s):

Younghoon Jang ◽

Chaochen Wang ◽

Aaron Broun ◽

Young-Kwon Park ◽

Lenan Zhuang ◽

...

Keyword(s):

Adipose Tissue ◽

Precursor Cells ◽

Tissue Development ◽

Set Domain ◽

H3k4 Methylation ◽

Double Knockout ◽

Histone H3k4 ◽

Adipose Tissue Development ◽

And Function ◽

H3k4 Methyltransferases

AbstractHistone H3K4 mono-methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. To address MLL3/4 enzymatic activity in enhancer regulation, we have generated two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domains. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and prevents adipogenesis and adipose tissue development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases. Notably, deletion of the enzymatic SET domain of MLL3/4 in lineage-specific precursor cells mimics H3.3K4M expression and prevents adipose tissue development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and function. Together, our findings indicate that H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development.

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Publisher Correction: Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

Communications Biology ◽

10.1038/s42003-020-1061-7 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Christina N. Vallianatos ◽

Brynne Raines ◽

Robert S. Porter ◽

Katherine M. Bonefas ◽

Michael C. Wu ◽

...

Keyword(s):

H3k4 Methylation ◽

Neuronal Structure ◽

Histone H3k4

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Regulation of subtelomeric fungal secondary metabolite genes by H3K4me3 regulators CclA and KdmB

10.26686/wgtn.13150928.v1 ◽

2020 ◽

Author(s):

Yonathan Lukito ◽

T Chujo ◽

TK Hale ◽

W Mace ◽

LJ Johnson ◽

...

Keyword(s):

Secondary Metabolite ◽

Transcriptional Activation ◽

Transcriptional Repression ◽

Target Genes ◽

H3k4 Methylation ◽

Genome Wide ◽

H3k4me3 Mark ◽

Transcriptional Changes ◽

Histone H3k4 ◽

A Site

© 2019 John Wiley & Sons Ltd Studies on the regulation of fungal secondary metabolism highlight the importance of histone H3K4 methylation regulators Set1, CclA (Ash2) and KdmB (KDM5), but it remains unclear whether these proteins act by direct modulation of H3K4me3 at the target genes. In filamentous fungi, secondary metabolite genes are frequently located near telomeres, a site where H3K4 methylation is thought to have a repressive role. Here we analyzed the role of CclA, KdmB and H3K4me3 in regulating the subtelomeric EAS and LTM cluster genes in Epichloë festucae. Depletion of H3K4me3 correlated with transcriptional activation of these genes in ΔcclA, similarly enrichment of H3K4me3 correlated with transcriptional repression of the genes in ΔkdmB which was accompanied by significant reduction in the levels of the agriculturally undesirable lolitrems. These transcriptional changes could only be explained by the alterations in H3K4me3 and not in the subtelomerically-important marks H3K9me3/K27me3. However, H3K4me3 changes in both mutants were not confined to these regions but occurred genome-wide, and at other subtelomeric loci there were inconsistent correlations between H3K4me3 enrichment and gene repression. Our study suggests that CclA and KdmB are crucial regulators of secondary metabolite genes, but these proteins likely act via means independent to, or in conjunction with the H3K4me3 mark.

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