An endoderm‐specific transcriptional enhancer from the mouse <i>Gata4</i> gene requires GATA and homeodomain protein–binding sites for function in vivo

Rojas, Anabel; Schachterle, William; Xu, Shan-Mei; Black, Brian L.

doi:10.1002/dvdy.22091

Cited by 29 publications

(36 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6E). The region with co-localized peaks at −80 kb was active selectively in the pancreas when tested in transgenic animals (Rojas et al, 2009). Most of these regulatory genes are known to affect the embryonic development of other organ systems, and therefore are also likely to be direct targets of NR5A2 that control aspects of pancreatic development.…”

Section: Effects On Acinar Developmental Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

et al. 2014

View full text Add to dashboard Cite

The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype.

show abstract

Section: Effects On Acinar Developmental Gene Expressionmentioning

confidence: 99%

“…The regions of these genes bound by NR5A2 are active pancreas-specific transcriptional enhancers in transgenic mice (Masui et al, 2007Rojas et al, 2009;Meredith et al, 2013) (Mei Jiang, T.G.D., G.H.S. and R.J.M., unpublished).…”

Section: Mpc and Pre-acinar Cell Expansionmentioning

confidence: 99%

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…40047440), Pmel17 (Image Clone ID 30541702) and Sox10 probes were all designed by cloning the full-length cDNA into pBlueScript. Immunofluorescence labeling of cryosections was performed as described previously (Rojas et al, 2009) using the following primary antibodies at 1:100 dilution in PBS with 3% BSA and 0.1% Triton X-100: anti-SOX10 (R&D AF2864); anti-MEF2C (C-17) (Santa Cruz, sc-13268); anti-DCT (alpha-PEP8).…”

Section: Generation and Analysis Of Transgenic Micementioning

confidence: 99%

The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10

et al. 2011

Self Cite

View full text Add to dashboard Cite

SUMMARYWaardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg-Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes.

show abstract

“…Functional enhancer redundancy for the genes regulated by such enhancers may, instead, be established by the presence of multiple independent enhancers with overlapping activities. This is particularly likely for Gata4, for which at least four separate enhancers have thus far been identified, including two with overlapping spatio-temporal activities [45,59,60].…”

Section: Discussionmentioning

confidence: 99%

Functional anatomy of distant-acting mammalian enhancers

Dickel

Visel

Pennacchio

2013

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

Transcriptional enhancers are a major class of functional element embedded in the vast non-coding portion of the human genome. Acting over large genomic distances, enhancers play critical roles in the tissue and cell type-specific regulation of genes, and there is mounting evidence that they contribute to the aetiology of many human diseases. Methods for genome-wide mapping of enhancer regions are now available, but the functional architecture contained within human enhancer elements remains unclear. Here, we review recent approaches aimed at understanding the functional anatomy of individual enhancer elements, using systematic qualitative and quantitative assessments of mammalian enhancer variants in cultured cells and in vivo . These studies provide direct insight into common architectural characteristics of enhancers including the presence of multiple transcription factor-binding sites and the mixture of both transcriptionally activating and repressing domains within the same enhancer. Despite such progress in understanding the functional composition of enhancers, the inherent complexities of enhancer anatomy continue to limit our ability to predict the impact of sequence changes on in vivo enhancer function. While providing an initial glimpse into the mutability of mammalian enhancers, these observations highlight the continued need for experimental enhancer assessment as genome sequencing becomes routine in the clinic.

show abstract

An endoderm‐specific transcriptional enhancer from the mouse Gata4 gene requires GATA and homeodomain protein–binding sites for function in vivo

Cited by 29 publications

References 71 publications

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10

Functional anatomy of distant-acting mammalian enhancers

Contact Info

Product

Resources

About