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A Role for hnRNP‐K in Regulating Open Chromatin in Embryonic Stem Cells

Review of “hnRNP-K targets open chromatin in mouse embryonic stem cells in concert with multiple regulators” from STEM CELLS by Stuart P. Atkinson

While the expression of the OCT4 transcription factor characterizes pluripotent stem cells, we still have an incomplete picture of the initiation of OCT4 gene expression and its maintenance during development. Researchers from the laboratory of Alexey N. Tomilin (Russian Academy of Sciences, St. Petersburg, Russia) recently sought to explore a role of hnRNP‐K in OCT4 gene expression, given several reports describing a role for hnRNP‐K in pluripotent stem cells and development [1-4]. hnRNP‐K itself is a KH‐domain poly(C)‐binding protein family member characterized by high‐affinity interactions with polycytosine strands in DNA and RNA [5].

In a new STEM CELLS article, Bakhmet et al. report that hnRNP‐K binds to regulatory elements within the Oct4 gene in mouse embryonic stem cells (mESCs); however, hnRNP‐K also displays genome-wide binding at regions that overlap with binding sites for several crucial transcription factors and histone modifications associated with transcriptionally permissive “open” chromatin [6]. While the authors failed to establish a role for hnRNP‐K in Oct4 gene expression, they hope that their findings will further our knowledge regarding the maintenance of the pluripotent state.

This new study discovered that while hnRNP‐K occupies distal and proximal enhancers of the Oct4 gene in mESCs, the modulation of hnRNP‐K levels failed to influence the initiation, maintenance, or downregulation of Oct4 gene expression. These findings, surprisingly, suggest that hnRNP‐K function plays no role in the establishment of cellular pluripotency. Instead, the study revealed that hnRNP‐K plays essential cell‐autonomous roles that help to maintain mESC proliferation and viability. ChIP‐seq analysis of genome-wide binding of hnRNP‐K in mESCs identified thousands of target sites displaying co-binding of hnRNP‐K with pluripotency-associated and general transcription factors, including TBP, Oct4, and Otx2, and a range of transcriptionally permissive histone modifications. Indeed, the authors discovered that hnRNP‐K localized exclusively within open chromatin, thereby suggesting that it may play a role in the maintenance of this chromatin state, thereby permitting access of transcriptional activators and repressors to regulatory regions of the genome.

Future research by the authors aims to clarify whether hnRNP‐K promotes the open chromatin conformation or whether the open chromatin conformation allows hnRNP‐K binding via the implementation of techniques such as ATAC-seq (Assay for Transposase Accessible Chromatin with high-throughput sequencing) or MNase-seq (Direct sequencing following MNase digestion).

For more on how Oct4, pluripotency, and al the new findings regarding hnRNP‐K and open chromatin, stay tuned to the Stem Cells Portal!

References 

  1. Chia N-Y, Chan Y-S, Feng B, et al., A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 2010;468:316.
  2. Lin N, Chang K-Y, Li Z, et al., An Evolutionarily Conserved Long Noncoding RNA TUNA Controls Pluripotency and Neural Lineage Commitment. Molecular Cell 2014;53:1005-1019.
  3. Thompson PJ, Dulberg V, Moon K-M, et al., hnRNP K Coordinates Transcriptional Silencing by SETDB1 in Embryonic Stem Cells. PLOS Genetics 2015;11:e1004933.
  4. Gallardo M, Lee Hun J, Zhang X, et al., hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies. Cancer Cell 2015;28:486-499.
  5. Backe PH, Messias AC, Ravelli RBG, et al., X-Ray Crystallographic and NMR Studies of the Third KH Domain of hnRNP K in Complex with Single-Stranded Nucleic Acids. Structure 2005;13:1055-1067.
  6. Bakhmet EI, Nazarov IB, Gazizova AR, et al., hnRNP-K Targets Open Chromatin in Mouse Embryonic Stem Cells in Concert with Multiple Regulators. STEM CELLS 2019;37:1018-1029.