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Breaking boundaries: Pan BETi disrupt 3D chromatin structure, BD2-selective BETi are strictly epigenetic transcriptional regulators.
Tsujikawa, Laura M; Kharenko, Olesya A; Stotz, Stephanie C; Rakai, Brooke D; Sarsons, Christopher D; Gilham, Dean; Wasiak, Sylwia; Fu, Li; Sweeney, Michael; Johansson, Jan O; Wong, Norman C W; Kulikowski, Ewelina.
  • Tsujikawa LM; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: laura@resverlogix.com.
  • Kharenko OA; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: olesya@resverlogix.com.
  • Stotz SC; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: sstotz@resverlogix.com.
  • Rakai BD; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: bdrakai@gmail.com.
  • Sarsons CD; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: chris@resverlogix.com.
  • Gilham D; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: dean@resverlogix.com.
  • Wasiak S; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: sylwia@resverlogix.com.
  • Fu L; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: li@resverlogix.com.
  • Sweeney M; Resverlogix Corporation, Suite 4010, 44 Montgomery Street, San Francisco, CA 94104, USA. Electronic address: msweeney@resverlogix.com.
  • Johansson JO; Resverlogix Corporation, Suite 4010, 44 Montgomery Street, San Francisco, CA 94104, USA. Electronic address: jan@resverlogix.com.
  • Wong NCW; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: norm@resverlogix.com.
  • Kulikowski E; Resverlogix Corporation, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada. Electronic address: ewelina@resverlogix.com.
Biomed Pharmacother ; 152: 113230, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1881709
ABSTRACT

BACKGROUND:

Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability.

METHODS:

Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNFα was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays.

FINDINGS:

We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription.

INTERPRETATION:

BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / COVID-19 Type of study: Experimental Studies Limits: Humans Language: English Journal: Biomed Pharmacother Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / COVID-19 Type of study: Experimental Studies Limits: Humans Language: English Journal: Biomed Pharmacother Year: 2022 Document Type: Article