Biology subjects

Bachu, M.

Publications and source records attributed to Bachu, M..

3 recordsLinked to original sources

bioRxiv2023

BRD4 directs mitotic cell division by inhibiting DNA damage

BRD4 binds to acetylated histones to regulate transcription and drive cancer cell proliferation. However, the role of BRD4 in normal cell growth remains to be elucidated. Here we investigated the question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells: they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. We suggest that BRD4 epigenetically marks those genes and serves as a master regulator of normal cell growth.

cell biology↗

bioRxiv2022

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

Regulation of endosomal TLR responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases. The current paradigm is that CXCL4 potentiates TLR responses by binding and facilitating endosomal delivery of nucleic acid TLR ligands. We report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively and dramatically amplifying inflammatory gene transcription and IL-1{beta} production, while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKK{varepsilon} and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for an exogenous activator of a second signal for IL-1{beta} maturation. CXCL4 signaling strongly induced chromatin remodeling and de novo enhancers associated with inflammatory genes in a cooperative and synergistic manner with TLR8. These findings identify new mechanisms of regulation of TLR responses relevant for cytokine storm, and suggest targeting the TBK1/IKK{varepsilon}-IRF5 axis may be beneficial in inflammatory diseases.

immunology↗

bioRxiv2020

Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Osteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C- monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8 deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation.

immunology↗