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Transcriptional Study Paves the Way for Novel Heart Regeneration Strategy

Review of “Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity” from Nature Communications by Stuart P. Atkinson

The Myc basic helix-loop-helix–leucine zipper transcription factor functions principally as a transcriptional activator to coordinate those programs underpinning normal cell function; furthermore, Myc also controls tissue-specific tissue regeneration programs [1-3]. Myc regulates the expression of a large proportion of genes and binds at virtually all promoters with an open chromatin architecture; therefore, the observed tissue-specific variations in Myc activity [4, 5] might derive from the engagement of specific, pre-configured resident cellular transcriptional programs.

Recently, researchers led by Gerard I. Evan and Catherine H. Wilson (University of Cambridge, Cambridge, UK) set out to understand the precise mechanisms controlling Myc-mediated transcriptional programs in various tissue types, and now, Bywater et al. report that Myc transcription depends on the levels of the positive transcription elongation factor (P-TEFb) complex, that is composed of cyclin-dependent kinase 9 (CDK9) and Cyclin T1 [6]. Furthermore, the authors also now establish that the overexpression of Myc and Cyclin T1 in the heart, which does not display a significant response following Myc overexpression, prompts cardiomyocyte proliferation.

The study employed a unique transgenic mouse model that inducibly expressed Myc at comparable levels across all tissues. While the induction of supraphysiological levels of Myc in tissues that display low levels of endogenous Myc and regeneration after injury (e.g., liver, lungs, and pancreas) prompted significant levels of cell proliferation, the induction of Myc in tissues that normally display low levels of endogenous Myc and regeneration (e.g., kidney, heart, and brain) prompted a negligible rise in cell proliferation. The authors established that Myc bound to open DNA elements in cells of the liver (Myc-responsive) and induced transcription following the induction of Myc expression; however, even though purified cardiomyocytes displayed only a modest elevation in transcription following Myc induction, Myc still bound to open chromatin elements. These findings suggested that the muted transcriptional/biological responses to Myc expression observed in the heart/cardiomyocytes may be due to either active transcriptional inhibition or the lack of transcriptional co-factors/machinery.

Myc transcription depends on the level of P-TEFb, and protein analysis established that the heart and kidney expressed low levels of both CDK9 and Cyclin T1 when compared with the lungs or liver; however, overexpression of Cyclin T1 in purified cardiomyocytes facilitated the transcription of previously unresponsive Myc target genes. The inducible proliferation of adult cardiomyocytes as a means to induce endogenous regeneration of the human infarcted heart represents one of the holy grails of regenerative medicine, and, excitingly, the authors finished their study by revealing that Myc expression in the presence of higher levels of active P-TEFb resulted in the proliferation and cytokinesis of cardiomyocytes in vivo, resulting in increased heart size and cardiomyocyte number within a short timeframe.

Collectively, these data provide an enhanced understanding of Myc transcriptional activity and establish that the concomitant expression of Myc and the P-TEFb transcriptional co-factor can induce cardiomyocyte proliferation in the adult mouse heart and so may pave the way for the development of novel cardiac regeneration strategies. 

For more details on Myc-mediated transcription and the development of new regenerative strategies for typically non-regenerative tissues, stay tuned to the Stem Cells Portal.

References

  1. Shchors K, Shchors E, Rostker F, et al., The Myc-dependent Angiogenic Switch in Tumors is Mediated by Interleukin 1β. Genes & Development 2006;20:2527-2538.
  2. Sodir NM, Swigart LB, Karnezis AN, et al., Endogenous Myc Maintains the Tumor Microenvironment. Genes & Development 2011;25:907-916.
  3. Kortlever RM, Sodir NM, Wilson CH, et al., Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell 2017;171:1301-1315.e14.
  4. Patel JH, Loboda AP, Showe MK, et al., Analysis of Genomic Targets Reveals Complex Functions of MYC. Nature Reviews Cancer 2004;4:562-568.
  5. Kress TR, Sabò A, and Amati B, MYC: Connecting Selective Transcriptional Control to Global RNA Production. Nature Reviews Cancer 2015;15:593-607.
  6. Bywater MJ, Burkhart DL, Straube J, et al., Reactivation of Myc Transcription in the Mouse Heart Unlocks its Proliferative Capacity. Nature Communications 2020;11:1827.