The Transcription Factor Neural Retina Leucine Zipper (NRL) Controls Photoreceptor-specific Expression of Myocyte Enhancer Factor Mef2c from an Alternative Promoter

Hong, Huasheng; Tummala, Padmaja; Guzmán, Eduardo Lozano; Mali, Raghuveer Singh; Gregorski, Janina; Swaroop, Anand; Mitton, Kenneth P.

doi:10.1074/jbc.m111.271072

Cited by 35 publications

(38 citation statements)

References 65 publications

(73 reference statements)

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“…Consistent with previous observations (Hao et al, 2011; Hao et al, 2014), we identified several rod-specific alternative transcript isoforms that are regulated by NRL. Hematopoietic cell-specific Lyn substrate 1 ( Hcls1 ), associated with gene regulation in the hematopoietic system (Skokowa et al, 2012), exhibited rod-specific, late onset expression of a transcript which is initiated upstream of exon 8 from a new transcription start site, suggesting alternative promoter usage (Figure 6C).…”

Section: Resultssupporting

confidence: 91%

“…A vast majority (672 out of 803) of TF-encoding transcripts was present in modules A, B and C, which included all known rod-specific transcriptional regulators (Figure S5). Analysis of module A yielded a sub-cluster of 12 TFs including Esrrb and Mef2C (Figure S5; Rod cluster), which are known regulators of rod differentiation (Hao et al, 2012; Hao et al, 2011; Onishi et al, 2010). The ‘rod cluster’ exhibited a clear shift in expression between P6 and P10, with no or low expression in the early postnatal days and a substantially higher expression by P10 and later.…”

Section: Resultsmentioning

confidence: 99%

“…A key downstream target of NRL, the orphan nuclear receptor NR2E3, actively suppresses cone genes and consolidates the rod cell fate (Cheng et al, 2006; Oh et al, 2008). In addition, estrogen-related receptor ESRRB, myocyte enhancer factor MEF2C, histone lysine-specific demethylase KDM5B and transcription-splicing protein NONO are among NRL targets that regulate specific aspects of rod development and survival (Hao et al, 2012; Hao et al, 2011; Onishi et al, 2010; Yadav et al, 2014). Thus, genome-wide targetome studies of NRL, CRX (Corbo et al, 2010; Hao et al, 2012), and other downstream TFs can be integrated with transcriptome profiles to assemble GRN modules associated with rod differentiation (Yang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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SUMMARY Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. As the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal day 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously un-annotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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“…EMSAs were performed as previously described (60). The method used for this study is described in the Supplemental Methods.…”

Section: Discussionmentioning

confidence: 99%

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

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106

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Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx Rip ). We determined that Crx Rip is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the Crx Rip phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in Crx Rip retinas. Expression of NRL partially restored rod development in Crx Rip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in Crx Rip mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.

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“…OTX2, RORβ, BLIMP1 (PRDM1) and CRX are among the regulatory proteins that are crucial for photoreceptor development ; however, two key transcription factors -NRL and TRβ2 (encoded by Thrb) -together determine the generation of three distinct types of photoreceptors (rods, S-cones and M-cones) from postmitotic precursors (Ng et al, 2011). Downstream targets of NRL and CRX, as well as signaling proteins that modify their activity, further modulate the expression of photoreceptor genes (Oh et al, 2008;Onishi et al, 2009;Onishi et al, 2010;Roger et al, 2010;Hao et al, 2011). Loss or altered function of these regulatory proteins results in photoreceptor dysfunction and retinal diseases Wright et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis

et al. 2013

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SUMMARYDysfunction or death of photoreceptors is the primary cause of vision loss in retinal and macular degenerative diseases. As photoreceptors have an intimate relationship with the retinal pigment epithelium (RPE) for exchange of macromolecules, removal of shed membrane discs and retinoid recycling, an improved understanding of the development of the photoreceptor-RPE complex will allow better design of gene-and cell-based therapies. To explore the epigenetic contribution to retinal development we generated conditional knockout alleles of DNA methyltransferase 1 (Dnmt1) in mice. Conditional Dnmt1 knockdown in early eye development mediated by Rx-Cre did not produce lamination or cell fate defects, except in cones; however, the photoreceptors completely lacked outer segments despite near normal expression of phototransduction and cilia genes. We also identified disruption of RPE morphology and polarization as early as E15.5. Defects in outer segment biogenesis were evident with Dnmt1 exon excision only in RPE, but not when excision was directed exclusively to photoreceptors. We detected a reduction in DNA methylation of LINE1 elements (a measure of global DNA methylation) in developing mutant RPE as compared with neural retina, and of Tuba3a, which exhibited dramatically increased expression in mutant retina. These results demonstrate a unique function of DNMT1-mediated DNA methylation in controlling RPE apicobasal polarity and neural retina differentiation. We also establish a model to study the epigenetic mechanisms and signaling pathways that guide the modulation of photoreceptor outer segment morphogenesis by RPE during retinal development and disease.

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The Transcription Factor Neural Retina Leucine Zipper (NRL) Controls Photoreceptor-specific Expression of Myocyte Enhancer Factor Mef2c from an Alternative Promoter

Cited by 35 publications

References 65 publications

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis

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