title: Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts.
abstract: Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target geneEbf1involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan , Ann Arbor, MI, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI, USA; Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Ienglam
authors.initials: I
authors.lastname: Lei
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
authors.forename: Yangbing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan , Ann Arbor, MI, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Gnatovskiy
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1301 Catherine , Ann Arbor, MI, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan , Ann Arbor, MI, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
keywords: Cardiac reprogramming; H3K4 methyltransferase; Mll1 inhibitor; adipocyte; cardiomyocyte