The polycomb group protein L3MBTL1 repreßes a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells

Fabiana Perna, Ly P. Vu, Maria Themeli, Sonja Kriks, Ruben Hoya-Arias, Raya Khanin, Todd Hricik, Jorge Mansilla-Soto, Eirini P. Papapetrou, Roß L. Levine, Lorenz Studer, Michel Sadelain, Stephen D. Nimer

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell pop-ulations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia.

Original languageEnglish (US)
Pages (from-to)658-669
Number of pages12
JournalStem Cell Reports
Volume4
Issue number4
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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    Perna, F., Vu, L. P., Themeli, M., Kriks, S., Hoya-Arias, R., Khanin, R., Hricik, T., Mansilla-Soto, J., Papapetrou, E. P., Levine, R. L., Studer, L., Sadelain, M., & Nimer, S. D. (2015). The polycomb group protein L3MBTL1 repreßes a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells. Stem Cell Reports, 4(4), 658-669. https://doi.org/10.1016/j.stemcr.2015.02.003