YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo

Monroe, Tanner O.; Hill, Matthew C.; Morikawa, Yuka; Leach, John P.; Heallen, Todd R.; Cao, Shuyi; Krijger, Peter H.L.; Laat, Wouter de; Wehrens, Xander H.T.; Rodney, George G.; Martin, James F.

doi:10.1016/j.devcel.2019.01.017

Cited by 177 publications

(174 citation statements)

References 99 publications

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“…This notion is consistent with our finding that LIN9 remains associated with promoters of cell cycle genes in postnatal hearts and with the observation that DREAM binds in human cells to a nucleosome-free region at transcriptional start sites upstream from regions with high nucleosome density (Marceau et al, 2016). Further support from such a model comes from the observation that cell cycle promoters, as opposed to genes that regulate cell-cell contacts and the cytoskeleton, are readily accessible in adult murine hearts before introduction of a YAP5SA transgene (Monroe et al, 2019). Thus, LIN9…”

Section: Discussionsupporting

confidence: 89%

“…YAP is known to promote proliferation of embryonic cardiomyocytes during development whereas inhibition of YAP by the Hippo cascade suppresses cardiomyocyte proliferation (Heallen et al, 2011;Xin et al, 2011;Gise et al, 2012). Activated YAP or loss of Hippo signaling can also extend the neonatal proliferation of cardiomyocytes to postnatal stages, where proliferation is normally very low (Gise et al, 2012;Heallen et al, 2011;Monroe et al, 2019). Whether MuvB impacts on the ability of YAP to regulate cardiomyocyte gene expression and to promote cardiomyocyte proliferation is unclear.…”

Section: Yap Interacts With Mmb In Cardiomyocytesmentioning

confidence: 99%

“…For example, cardiac-specific deletion of the Hippo kinases LATS1/2 or the scaffold protein SAV1 results in heart enlargement and increased proliferation of embryonal and postnatal cardiomyocytes due to increased YAP activity (Heallen et al, 2011;Heallen et al, 2013). Furthermore, expression of active YAP promotes proliferation of postnatal cardiomyocytes and induces a fetal-like cell state in adult cardiomyocytes (Gise et al, 2012;Monroe et al, 2019). Conversely, deletion of YAP in the embryonic heart reduces cardiomyocyte proliferation and results in myocardial hypoplasia and embryonic lethality (Xin et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Gründl

Walz

Hauf

et al. 2019

Preprint

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YAP, a major downstream effector of the Hippo signaling pathway, is an important regulator of cell proliferation. The ability of YAP to regulate G2/M gene expression is dependent on the Myb-MuvB (MMB) complex, consisting of the evolutionary MuvB core complex and the facultative B-MYB subunit, a transcription factor. Here we show that YAP directly binds to B-MYB. Disruption of the YAP/B-MYB interaction by overexpression of the YAP binding domain of B-MYB results in errors in cell division. We also show that YAP and MMB interact in vivo in the developing heart. Genome studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Cardiac specific deletion of the LIN9 subunit of MMB prevents the upregulation of cell cycle genes and the increased proliferation of cardiomyocytes lacking the Hippo-signaling component SAV1. Similarly, we find that proliferation of postnatal cardiomyocytes induced by constitutive active YAP depends on MMB. Our findings provide new insights in the YAP induced proliferation of cardiomyocytes through the functional interaction with MMB.

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Section: Discussionsupporting

confidence: 89%

Section: Yap Interacts With Mmb In Cardiomyocytesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Gründl

Walz

Hauf

et al. 2019

Preprint

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“…However, the exact mechanisms by which oncostatin M induces dedifferentiation are unclear. Inhibition of components of the Hippo pathway have also been shown to enhance cardiomyocyte proliferation by releasing the inactivation of this pathway that occurs during terminal differentiation (Xin et al, 2013, Lin et al, 2014, Leach et al, 2017, Monroe et al, 2019. A recent study demonstrated that the pro-proliferative effects of a Hippo resistant form of YAP were mediated by the reversion of cardiomyocytes to a foetal-like state by epigenetic remodelling of chromatin (Monroe et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Transient Reprogramming of Neonatal Cardiomyocytes to a Proliferative Dedifferentiated State

Kisby

Lázaro

Stylianou

et al. 2019

Preprint

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Zebrafish and urodele amphibians are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through transient expression of Oct3/4, Sox2, Klf4 and c-Myc (OSKM) transcription factors. Here, we utilized an OSKMencoding non-integrating vector to induce transient reprogramming of mammalian cardiomyocytes in vitro. Reprogramming factor expression in neonatal rat cardiomyocytes triggered rapid cell dedifferentiation characterized by downregulation of cardiomyocyte specific gene and protein expression, sarcomere dis-assembly and loss of autorhythmic contractile activity. Concomitantly, a significant increase in cell cycle related gene expression and Ki67 positive cells was observed, indicating that dedifferentiated cardiomyocytes possess an enhanced proliferative capacity. A small proportion of cardiomyocytes progressed through mesenchymal to epithelial transition, further indicating the initiation of cell reprogramming. However, complete reprogramming to a pluripotent-like state was not achieved for the duration of the study (20 days), both in standard and embryonic stem cell culture media conditions. The transient nature of this partial reprogramming response was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were recovered by day 15 after viral transduction. Further investigations into the complete downstream biological effects of ectopic OSKM expression in cardiomyocytes and the fate of these reprogrammed cells are warranted. Our results to date suggest that transient reprogramming could be a feasible strategy to recapitulate regenerative mechanisms of lower vertebrates and inform direct gene therapy approaches to cardiac regenerative medicine.

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“…The regenerative potential of the Hippo pathway has become abundantly clear in numerous organs, including the heart 5, [14][15][16] , retina 17 , liver, and intestine 18 . We earlier demonstrated that Hippo signaling limits the size of the developing murine utricle, a vestibular sensory organ, and that the Yap-Tead complex is active during-and necessary for-proliferative regeneration in the neonatal utricle 19 .…”

Section: Introductionmentioning

confidence: 99%

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Kastan

Gnedeva

Alisch

et al. 2020

Preprint

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Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs 1-3 . Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yapdependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cellspecific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. This project was made possible by the dedicated personnel of two service facilities. At Rockefeller University's High-Throughput Screening Resource Center directed by Fraser Glickman, Carolina Adura Alcaino helped design assays for enzyme activity. assisted with assay design and Rui Liang performed chemical syntheses. Declaration of InterestsKG, NK, TA, AAP, and AJH are parties to an application for patent protection of derivatives of the Lats inhibitor presented here.

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YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo

Cited by 177 publications

References 99 publications

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes

Transient Reprogramming of Neonatal Cardiomyocytes to a Proliferative Dedifferentiated State

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

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