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Index and biological spectrum of human DNase I hypersensitive sites.

ABSTRACT: DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA^1-5 and contain genetic variations associated with diseases and phenotypic traits^6-8. We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence, providing a common coordinate system for regulatory DNA. Here we show that these maps highly resolve the cis-regulatory compartment of the human genome, which encodes unexpectedly diverse cell- and tissue-selective regulatory programs at very high density. These programs can be captured comprehensively by a simple vocabulary that enables the assignment to each DHS of a regulatory barcode that encapsulates its tissue manifestations, and global annotation of protein-coding and non-coding RNA genes in a manner orthogonal to gene expression. Finally, we show that sharply resolved DHSs markedly enhance the genetic association and heritability signals of diseases and traits. Rather than being confined to a small number of distal elements or promoters, we find that genetic signals converge on congruently regulated sets of DHSs that decorate entire gene bodies. Together, our results create a universal, extensible coordinate system and vocabulary for human regulatory DNA marked by DHSs, and provide a new global perspective on the architecture of human gene regulation.

SUBMITTER: Meuleman W

PROVIDER: S-EPMC7422677 | 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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Index and biological spectrum of human DNase I hypersensitive sites.

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