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Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21

Jasmine Manji1,2, Jasmine Pipella1,2, Gabriel Brawerman1,2

  • 1Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada.

Epigenomes
|March 27, 2024
PubMed

Insights

Type 1 diabetes involves beta cell senescence and SASP. Bromodomain extra-terminal (BET) protein Brd4 interacts with chromatin remodelers in senescent beta cells, suggesting a role in regulating this process.

Area of Science:

  • Endocrinology
  • Immunology
  • Cell Biology

Background:

  • Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells.
  • A subset of these beta cells enters senescence, a state marked by growth arrest and a senescence-associated secretory phenotype (SASP).
  • Transcriptional regulation of SASP by bromodomain extra-terminal (BET) proteins in T1D beta cells is not fully understood.

Purpose of the Study:

  • To investigate the transcriptional mechanisms regulating beta cell senescence and SASP in Type 1 diabetes.
  • To identify binding partners of the BET protein Brd4 in senescent beta cells.
  • To explore the role of p21 in beta cell senescence and SASP.

Main Methods:

  • Utilized the NIT-1 cell line, a NOD mouse model of T1D beta cell senescence.
  • Identified Brd4 interacting proteins using co-immunoprecipitation and mass spectrometry.
  • Analyzed single-cell RNA-seq data from mouse and human islets.
  • Performed RNAi knockdown of p21 in senescent NIT-1 cells.

Main Results:

  • Brd4 interacted with components of the Ino80 chromatin remodeling complex in senescent NIT-1 cells.
  • Ino80 complex subunits were expressed in beta cells during T1D progression in NOD mice and in human islets.
  • Knockdown of p21 did not significantly affect beta cell viability or SASP induction.

Conclusions:

  • Brd4 interacts with protein partners, potentially including chromatin remodelers, during beta cell senescence.
  • These interactions may contribute to the transcriptional activation of SASP genes.
  • p21 is not essential for SASP in this beta cell senescence model.
Keywords:
SASPbromodomain extra-terminal domain proteinscellular senescencepancreatic beta cellstype 1 diabetes

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