scholarly journals bHLH Transcription Factor Math6 Antagonizes TGF-β Signalling in Reprogramming, Pluripotency and Early Cell Fate Decisions

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 529 ◽  
Author(s):  
Satya Srirama Karthik Divvela ◽  
Patrick Nell ◽  
Markus Napirei ◽  
Holm Zaehres ◽  
Jiayu Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Cellular Reprogramming ◽  
Bhlh Transcription Factor ◽  
Tgf Beta ◽  
Cell Fate Decisions ◽  
Helix Loop Helix ◽  
Induced Pluripotent

The basic helix-loop-helix (bHLH) transcription factor Math6 (Atonal homolog 8; Atoh8) plays a crucial role in a number of cellular processes during embryonic development, iron metabolism and tumorigenesis. We report here on its involvement in cellular reprogramming from fibroblasts to induced pluripotent stem cells, in the maintenance of pluripotency and in early fate decisions during murine development. Loss of Math6 disrupts mesenchymal-to-epithelial transition during reprogramming and primes pluripotent stem cells towards the mesendodermal fate. Math6 can thus be considered a regulator of reprogramming and pluripotent stem cell fate. Additionally, our results demonstrate the involvement of Math6 in SMAD-dependent TGF beta signalling. We furthermore monitor the presence of the Math6 protein during these developmental processes using a newly generated Math6Flag-tag mouse. Taken together, our results suggest that Math6 counteracts TGF beta signalling and, by this, affects the initiating step of cellular reprogramming, as well as the maintenance of pluripotency and early differentiation.

scholarly journals SUMO maintains the chromatin environment of human induced pluripotent stem cells

2020 ◽  
Author(s):  
Barbara Mojsa ◽  
Michael H. Tatham ◽  
Lindsay Davidson ◽  
Magda Liczmanska ◽  
Jane E. Wright ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Transcriptional Start Site ◽  
Chromatin Accessibility ◽  
Covalent Attachment ◽  
Cell Fate Decisions ◽  
Sumo Modification ◽  
Induced Pluripotent

AbstractPluripotent stem cells represent a powerful system to identify the mechanisms governing cell fate decisions during early mammalian development. Covalent attachment of the Small Ubiquitin Like Modifier (SUMO) to proteins has emerged as an important factor in stem cell maintenance. Here we show that SUMO is required to maintain stem cells in their pluripotent state and identify many chromatin-associated proteins as bona fide SUMO substrates in human induced pluripotent stem cells (hiPSCs). Loss of SUMO increases chromatin accessibility and expression of long non-coding RNAs and human endogenous retroviral elements, indicating a role for the SUMO modification of SETDB1 and a large TRIM28 centric network of zinc finger proteins in silencing of these elements. While most protein coding genes are unaffected, the Preferentially Expressed Antigen of Melanoma (PRAME) gene locus becomes more accessible and transcription is dramatically increased after inhibition of SUMO modification. When PRAME is silent, a peak of SUMO over the transcriptional start site overlaps with ChIP-seq peaks for cohesin, RNA pol II, CTCF and ZNF143, with the latter two heavily modified by SUMO. These associations suggest that silencing of the PRAME gene is maintained by the influence of SUMO on higher order chromatin structure. Our data indicate that SUMO modification plays an important role in hiPSCs by repressing genes that disrupt pluripotency networks or drive differentiation.

Signaling Pathways Controlling Pluripotency and Early Cell Fate Decisions of Human Induced Pluripotent Stem Cells

Stem Cells ◽  
2009 ◽  
Vol 27 (11) ◽  
pp. 2655-2666 ◽  
Author(s):  
Ludovic Vallier ◽  
Thomas Touboul ◽  
Stephanie Brown ◽  
Candy Cho ◽  
Bilada Bilican ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Cell Fate Decisions ◽  
Induced Pluripotent

scholarly journals Research and therapy with induced pluripotent stem cells (iPSCs): social, legal, and ethical considerations

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sharif Moradi ◽  
Hamid Mahdizadeh ◽  
Tomo Šarić ◽  
Johnny Kim ◽  
Javad Harati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Healthy Person ◽  
New Drugs ◽  
Full Potential ◽  
Cell Fate Decisions ◽  
Induced Pluripotent

AbstractInduced pluripotent stem cells (iPSCs) can self-renew indefinitely in culture and differentiate into all specialized cell types including gametes. iPSCs do not exist naturally and are instead generated (“induced” or “reprogrammed”) in culture from somatic cells through ectopic co-expression of defined pluripotency factors. Since they can be generated from any healthy person or patient, iPSCs are considered as a valuable resource for regenerative medicine to replace diseased or damaged tissues. In addition, reprogramming technology has provided a powerful tool to study mechanisms of cell fate decisions and to model human diseases, thereby substantially potentiating the possibility to (i) discover new drugs in screening formats and (ii) treat life-threatening diseases through cell therapy-based strategies. However, various legal and ethical barriers arise when aiming to exploit the full potential of iPSCs to minimize abuse or unauthorized utilization. In this review, we discuss bioethical, legal, and societal concerns associated with research and therapy using iPSCs. Furthermore, we present key questions and suggestions for stem cell scientists, legal authorities, and social activists investigating and working in this field.

scholarly journals Noncanonical NOTCH Signaling Limits Self-Renewal of Human Epithelial and Induced Pluripotent Stem Cells through ROCK Activation

2013 ◽  
Vol 33 (22) ◽  
pp. 4434-4447 ◽  
Author(s):  
Takashi Yugawa ◽  
Koichiro Nishino ◽  
Shin-ichi Ohno ◽  
Tomomi Nakahara ◽  
Masatoshi Fujita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Human Keratinocytes ◽  
Small Gtpase ◽  
Keratinocyte Differentiation ◽  
Growth Defect ◽  
Self Renewal ◽  
Induced Pluripotent

NOTCH plays essential roles in cell fate specification during embryonic development and in adult tissue maintenance. In keratinocytes, it is a key inducer of differentiation. ROCK, an effector of the small GTPase Rho, is also implicated in keratinocyte differentiation, and its inhibition efficiently potentiates immortalization of human keratinocytes and greatly improves survival of dissociated human pluripotent stem cells. However, the molecular basis for ROCK activation is not fully established in these contexts. Here we provide evidence that intracellular forms of NOTCH1 trigger the immediate activation of ROCK1 independent of its transcriptional activity, promoting differentiation and resulting in decreased clonogenicity of normal human keratinocytes. Knockdown of NOTCH1 abrogated ROCK1 activation and conferred sustained clonogenicity upon differentiation stimuli. Treatment with a ROCK inhibitor, Y-27632, or ROCK1 silencing substantially rescued the growth defect induced by activated NOTCH1. Furthermore, we revealed that impaired self-renewal of human induced pluripotent stem cells upon dissociation is, at least in part, attributable to NOTCH-dependent ROCK activation. Thus, the present study unveils a novel NOTCH-ROCK pathway critical for cellular differentiation and loss of self-renewal capacity in a subset of immature cells.

scholarly journals Single Transcription Factor Reprogramming of Hair Follicle Dermal Papilla Cells to Induced Pluripotent Stem Cells

Stem Cells ◽  
2011 ◽  
Vol 29 (6) ◽  
pp. 964-971 ◽  
Author(s):  
Su-Yi Tsai ◽  
Britta Am Bouwman ◽  
Yen-Sin Ang ◽  
Soo Jeong Kim ◽  
Dung-Fang Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Induced Pluripotent Stem Cells ◽  
Hair Follicle ◽  
Pluripotent Stem Cells ◽  
Dermal Papilla ◽  
Dermal Papilla Cells ◽  
Induced Pluripotent

scholarly journals Grasses use an alternatively wired bHLH transcription factor network to establish stomatal identity

2016 ◽  
Vol 113 (29) ◽  
pp. 8326-8331 ◽  
Author(s):  
Michael T. Raissig ◽  
Emily Abrash ◽  
Akhila Bettadapur ◽  
John P. Vogel ◽  
Dominique C. Bergmann
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Brachypodium Distachyon ◽  
Bhlh Transcription Factor ◽  
Stomatal Development ◽  
Helix Loop Helix ◽  
Factor Module ◽  
Forward Genetic Screens ◽  
Conserved Genes ◽  
And Behavior

Stomata, epidermal valves facilitating plant–atmosphere gas exchange, represent a powerful model for understanding cell fate and pattern in plants. Core basic helix–loop–helix (bHLH) transcription factors regulating stomatal development were identified in Arabidopsis, but this dicot’s developmental pattern and stomatal morphology represent only one of many possibilities in nature. Here, using unbiased forward genetic screens, followed by analysis of reporters and engineered mutants, we show that stomatal initiation in the grass Brachypodium distachyon uses orthologs of stomatal regulators known from Arabidopsis but that the function and behavior of individual genes, the relationships among genes, and the regulation of their protein products have diverged. Our results highlight ways in which a kernel of conserved genes may be alternatively wired to produce diversity in patterning and morphology and suggest that the stomatal transcription factor module is a prime target for breeding or genome modification to improve plant productivity.

scholarly journals Dot1L methyltransferase activity is a barrier to acquisition of pluripotency but not transdifferentiation

2019 ◽  
Author(s):  
Coral K. Wille ◽  
Rupa Sridharan
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Transcriptional Elongation ◽  
Mrna Levels ◽  
Mesenchymal To Epithelial Transition ◽  
Ipsc Generation ◽  
Induced Pluripotent

ABSTRACTThe ability of pluripotent stem cells to be poised to differentiate into any somatic cell type is partly derived from a unique chromatin structure that is depleted for transcriptional elongation associated epigenetic modifications, primarily H3K79 methylation. Inhibiting the H3K79 methyltransferase, Dot1L, increases the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) most potently at the mid-point of the process. Surprisingly, despite the enrichment of H3K79me2 on thousands of actively transcribed genes, Dot1L inhibition (Dot1Li) results in few changes in steady state mRNA levels during reprogramming. Dot1Li spuriously upregulates genes not involved in pluripotency and does not shutdown the somatic program. Depletion of the few genes that are downregulated, such as Nfix, enhances reprogramming efficiency in cooperation with Dot1Li. Contrary to the prevalent view, Dot1Li promotes iPSC generation beyond early phases of reprogramming such as the mesenchymal to epithelial transition and from already epithelial cell types including keratinocytes. Significantly, Dot1L inhibition does not enhance lineage conversion to neurons or muscle cells. Taken together, our results indicate that H3K79me is not a universal barrier of cell fate transitions but specifically protects somatic cells from reverting to the pluripotent state.

scholarly journals Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Elliot A Perens ◽  
Zayra V Garavito-Aguilar ◽  
Gina P Guio-Vega ◽  
Karen T Peña ◽  
Yocheved L Schindler ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Kidney Development ◽  
Bhlh Transcription Factor ◽  
Lateral Boundary ◽  
Zinc Finger Transcription Factor ◽  
Cell Fate Decisions ◽  
Intermediate Mesoderm ◽  
Vein Formation

Proper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. Here, we show that the bHLH transcription factor Hand2 limits the size of the embryonic kidney by restricting IM dimensions. The IM is expanded in zebrafish hand2 mutants and is diminished when hand2 is overexpressed. Within the posterior mesoderm, hand2 is expressed laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous development while inhibiting IM formation at this interface. Furthermore, hand2 and the co-expressed zinc-finger transcription factor osr1 have functionally antagonistic influences on kidney development. Together, our data suggest that hand2 functions in opposition to osr1 to balance the formation of kidney and vein progenitors by regulating cell fate decisions at the lateral boundary of the IM.

scholarly journals Hand2 Inhibits Kidney Specification While Promoting Vein Formation Within the Posterior Mesoderm

2016 ◽  
Author(s):  
Elliot A. Perens ◽  
Zayra V. Garavito-Aguilar ◽  
Gina P. Guio-Vega ◽  
Karen T. Peña ◽  
Yocheved L. Schindler ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Kidney Development ◽  
Bhlh Transcription Factor ◽  
Lateral Boundary ◽  
Zinc Finger Transcription Factor ◽  
Cell Fate Decisions ◽  
Intermediate Mesoderm ◽  
Vein Formation

AbstractProper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. Here, we show that the bHLH transcription factor Hand2 limits the size of the embryonic kidneyby restricting IM dimensions. The IM is expanded in zebrafish hand2 mutants and is diminished when hand2 is overexpressed. Within the posterior mesoderm, hand2 is expressed laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous development while inhibiting IM formation at this interface. Furthermore, hand2 and the co-expressed zinc-finger transcription factor osr1 have functionally antagonistic influences on kidney development. Together, our data suggest that hand2 functions in opposition to osr1 to balance the formation of kidney and vein progenitors by regulating cell fate decisions at the lateral boundary of the IM.IMPACT STATEMENTThe Hand2 transcription factor regulates the dimensions of the kidney by controlling cell fate decisions at the interface between organ fields.

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