Developmental Fate and Cellular Maturity Encoded in Human Regulatory DNA Landscapes

Stergachis, Andrew B.; Neph, Shane; Reynolds, Alex; Humbert, Richard; Miller, Brady; Paige, Sharon L.; Vernot, Benjamin; Cheng, Jeffrey B.; Thurman, Robert E.; Sandstrom, Richard; Haugen, Eric; Heimfeld, Shelly; Murry, Charles E.; Akey, Joshua M.; Stamatoyannopoulos, J

doi:10.1016/j.cell.2013.07.020

Cited by 328 publications

(358 citation statements)

References 54 publications

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“…While some enhancers are conserved from pluripotent to differentiated cell types, others are lost or created (Stergachis et al , 2013). Indeed, a noteworthy conclusion from our ChIP‐Seq analysis is that the early steps in differentiation are dominated by a loss of regulatory elements.…”

Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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“…Six1 is normally repressed by Ezh2, which functions to stabilize cardiac gene expression upon differentiation and to maintain postnatal cardiac homeostasis [81,82]. However, deletion of Ezh2 in differentiated cardiomyocytes does not cause any overt phenotype, which could be due to functional redundancy with Ezh1 at later stages of development [79].…”

Section: Histone Methyltrasnferases Are Required For Cardiomyocyte Prmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyoctes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigentic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury.

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“…As alluded to above, other levels of regulation are important-these include combinatorial coding, noncoding RNAs (ncRNAs), long-and short-range epigenetic control through modifications to chromatin and DNA, DNA looping, and the establishment of insulators, boundary elements, and specialized nuclear compartments (Spitz and Furlong 2012). There is still much discussion about which of these events are primary and causal, and which are consequences of TF binding (Spitz and Furlong 2012;Stergachis et al 2013). This highlights our poor understanding of the structure and function of the noncoding parts of the genome.…”

Section: A Network View Of Biologymentioning

confidence: 99%

Genetic Networks Governing Heart Development

Waardenberg

Ramialison

Bouveret

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Animal genomes contain a code for construction of the body plan from a fertilized egg. Understanding how genome information is deciphered to create the complex multilayered regulatory systems that drive organismal development, and which become altered in disease, is one of the greatest challenges in the biological sciences. The development of methods that effectively represent and communicate the complexity inherent in gene regulatory networks remains a major barrier. This review introduces the philosophy of systems biology and discusses recent progress in understanding the development of the heart at a systems biology level. SYSTEMS BIOLOGYS ystems biology is an emerging multidisciplinary field embedded in large-scale data initiatives that seeks to understand the complex interactions occurring within biological systems. The recent increase in popularity of systems biology has been the consequence of technological advances that have flowed from the sequencing of the human genome (Lander et al. 2001). However, the last decade of research has reinforced the notion that to understand biological networks we need to do more than just describe genome organization. A major finding that has reshaped our view of biology is the realization that transcriptional complexity rather than genome size or the number of protein-coding genes is the evolutionary driver for increased biological diversity (Britten and Davidson 1969;Carninci et al. 2005;Fantom Consortium et al. 2014).Network theory hypothesizes that specific interaction patterns in biology have logic and functional significance. The discovery that uni-

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Developmental Fate and Cellular Maturity Encoded in Human Regulatory DNA Landscapes

Cited by 328 publications

References 54 publications

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Resetting the epigenome for heart regeneration.

Genetic Networks Governing Heart Development

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