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The chromatin modifying enzyme LSD1 primes pancreatic progenitors for endocrine cell formation independent of NRSF activity

  • Author(s): Patel, Nisha A.
  • et al.

In recent years, pancreatic islet cell transplantation has become a viable option to eliminate the need for frequent insulin injections in type I diabetic patients. However, the shortage of organ donors limits widespread use of this therapy. There is hope that this limitation can be overcome by generating transplantable replacement insulin- producing beta-cells from human embryonic stem cells (hESCs). Studies of pancreas development in genetically engineered mice have provided the foundation for developing conditions that instruct hESCs to differentiate into pancreatic progenitors and beta-cells. While pancreatic progenitors can be efficiently generated in vitro, the efficiency of endocrine cell differentiation from these progenitors is still very low, thus compromising development of a cell-based therapy. Therefore, further developmental studies are crucial to identify the molecular cues that regulate the switch from a pancreatic progenitor to a committed endocrine cell. Here, I investigated the role of the transcription factor NRSF and a component in the NRSF corepressor complex, the histone demethylase LSD1, during pancreatic endocrine cell formation. Using in vitro and in vivo models of pancreas development, we show that NRSF is specifically repressed in endocrine cells and late progenitors committed to the endocrine fate. In pancreatic progenitors, NRSF occupies the regulatory regions of endocrine lineage-determining transcription factors. However, genetic ablation of NRSF revealed that NRSF is dispensable for pancreatic endocrine cell formation and function. In stark contrast, we show that the expression of LSD1, which has been shown to interact with a number of complexes, including the NRSF corepressor complex, is required for pancreatic endocrine cell formation. Genetic inactivation of Lsd1 in pancreatic progenitors leads to selective loss of the endocrine cell lineage, but only during a short competence window, which precedes endocrine cell differentiation by several days. Chromatin profiling of LSD1-deficient progenitors at the end of this competence window revealed a novel role for LSD1 in facilitating enhancer activation. These data suggest that transcription factors are not necessarily the only drivers of cell fate and that chromatin remodelers can also orchestrate cell fate decisions. Further, many factors have been thought to be master regulators of cell fate decisions, but LSD1 is the only factor to date that affects cell fate in multipotent progenitor cells prior to and independent of specification factors. Altogether, my findings not only uncover novel roles for these two genes during pancreatic endocrine cell formation, but also contribute to our basic understanding of how transcription factors and chromatin-modifying enzymes affect cell fate

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