title: MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency.
abstract: The interconversion between naive and primed pluripotent states is accompanied by drastic epigenetic rearrangements. However, it is unclear whether intrinsic epigenetic events can drive reprogramming to naive pluripotency or if distinct chromatin states are instead simply a reflection of discrete pluripotent states. Here, we show that blocking histone H3K4 methyltransferase MLL1 activity with the small-molecule inhibitor MM-401 reprograms mouse epiblast stem cells (EpiSCs) to naive pluripotency. This reversion is highly efficient and synchronized, with more than 50% of treated EpiSCs exhibiting features of naive embryonic stem cells (ESCs) within 3 days. Reverted ESCs reactivate the silenced X chromosome and contribute to embryos following blastocyst injection, generating germline-competent chimeras. Importantly, blocking MLL1 leads to global redistribution of H3K4me1 at enhancers and represses lineage determinant factors and EpiSC markers, which indirectly regulate ESC transcription circuitry. These findings show that discrete perturbation of H3K4 methylation is sufficient to drive reprogramming to naive pluripotency.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Srimonta
authors.initials: S
authors.lastname: Gayen
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Avinash K
authors.initials: AK
authors.lastname: Shanmugam
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.affiliation: Department of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Rajesh C
authors.initials: RC
authors.lastname: Rao
authors.affiliation: Department of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Kalantry
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: yalid@umich.edu.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
mesh_terms: D000818:Animals; D002460:Cell Line; D065150:Cellular Reprogramming / Q000187:drug effects*; D005855:Germ Layers / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: C587684:MM-401; D009842:Oligopeptides; D054852:Small Molecule Libraries; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse