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Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers.

ABSTRACT: Super-enhancers (SEs), which consist of multiple enhancer elements, are occupied by master transcription factors and co-activators, such as Mediator, and are highly acetylated at histone H3K27. Here, we have characterized the SEs in terms of DNase I hypersensitive sites (DHSs) by analyzing publicly available chromatin immunoprecipitation (ChIP)-seq and DNase-seq data of K562 cells and compared with the DHSs in typical enhancers (TEs). DHSs in the SEs were highly marked by histone H3K4me1 than DHSs in TEs. Loss of H3K4me1 by the deletion of catalytic domains in histone methyltransferases MLL3 and MLL4 remarkably decreased histone H3K27ac and histone H3 depletion at SE DHSs than at TE DHSs. The levels of enhancer RNA (eRNA) transcripts and mRNA transcripts from the putative target genes were notably reduced at and near SE DHSs than TE DHSs following H3K4me1 loss. These results indicate that histone H3K4me1 is a marker for DHSs in SEs and that this modification has a more significant impact on the activation of SE DHSs than TE DHSs.

SUBMITTER: Kang Y

PROVIDER: S-EPMC8264496 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Clarification of the mechanisms underlying osteoclast differentiation enable us to understand the physiology of bone metabolism as well as the pathophysiology of bone diseases, such as osteoporosis. Recently, it has been reported that epigenetics can determine the cell fate and regulate cell type specific gene expression. However, little is known about epigenetics during osteoclastogenesis. To reveal a part of epigenetics, especially focused on chromatin dynamics, during early osteoclastogenesis and identify novel transcription factors involved in osteoclastogenesis, we investigated genome-wide analysis of open chromatin during receptor activator of nuclear factor-M-NM-:B ligand (RANKL)-induced osteoclastogenesis using DNase I hypersensitive sites sequencing (DNase-seq). DNase-seq was performed using the extracted nuclei obtained from RAW264 cells treated with or without RANKL for 24 hours, followed by several bioinformatic analyses. DNase I hypersensitive sites (DHSs) during RANKL-induced osteoclastogenesis were dynamically changed and accumulated in promoter regions, although the distributions of DHSs among cis-regulatory DNA regions were identical regardless of RANKL stimulation. Motif discoveries from DHSs successfully identified well-known osteoclastogenic transcription factors such as Jun, CREB1, FOS, ATF2 and ATF4, but also novel transcription factors for osteoclastogenesis such as Zscan10, Atf1 Nrf1 and Srebf2. siRNA knockdown of these identified novel transcription factors impaired osteoclastogenesis. Taken together, DNase-seq can be a useful tool for comprehension of epigenetics, especially chromatin dynamics during osteoclastogenesis and for identification of novel transcription factors involved in osteoclastogenesis. This study may reveal underlying mechanisms that determine cell-type specific differentiation of bone cells and may lead to investigate novel therapeutic targets for osteoporosis. Examination of genome-wide DNase Hypersensitive Sites in differentiated and undifferentiated RAW264 cells.

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Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers.

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