ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit

TERZİ ÇİZMECİOĞLU N., Huang J., Keskin E. G., Wang X., Esen I., Chen F., ...More

JOURNAL OF BIOLOGICAL CHEMISTRY, vol.295, no.51, pp.17738-17751, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 295 Issue: 51
  • Publication Date: 2020
  • Doi Number: 10.1074/jbc.ra120.015534
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Applied Science & Technology Source, Aquatic Science & Fisheries Abstracts (ASFA), Artic & Antarctic Regions, BIOSIS, CAB Abstracts, Compendex, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.17738-17751
  • Keywords: embryonic stem cell, cell differentiation, epigenetics, gene expression, chromatin modification, embryonic stem cell, CHROMATIN REMODELING COMPLEX, HISTONE DEACETYLASE, SELF-RENEWAL, DEVELOPMENTAL REGULATORS, H3K4 TRIMETHYLATION, SUPER-ENHANCERS, GENE-EXPRESSION, RBP1 RECRUITS, RNAI SCREEN, POLYCOMB
  • Middle East Technical University Affiliated: Yes


Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit.