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Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts
Liu L.3; Lei I.3; Karatas H.2; Li Y.2; Wang L.1; Gnatovskiy L.3; Dou Y.2; Wang S.2; Qian L.1; Wang Z.3
2016-10-11
Source PublicationCell Discovery
ISSN20565968
Volume2
AbstractGeneration 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 gene Ebf1 involved 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.
Keywordadipocyte Cardiac reprogramming cardiomyocyte H3K4 methyltransferase Mll1 inhibitor
DOI10.1038/celldisc.2016.36
URLView the original
Language英語
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Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.The University of North Carolina at Chapel Hill
2.University of Michigan Medical School
3.University of Michigan, Ann Arbor
4.Universidade de Macau
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GB/T 7714
Liu L.,Lei I.,Karatas H.,et al. Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts[J]. Cell Discovery,2016,2.
APA Liu L..,Lei I..,Karatas H..,Li Y..,Wang L..,...&Wang Z..(2016).Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts.Cell Discovery,2.
MLA Liu L.,et al."Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts".Cell Discovery 2(2016).
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