Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm

Yang, Xinan; Nadadur, Rangarajan D.; Hilvering, Catharina R.E.; Bianchi, Valerio; Werner, Michael S.; Mazurek, Stefan R.; Gadek, Margaret; Shen, Karen; Goldman, Joseph D.; Tyan, Leonid; Bekeny, Jenna C.; Hall, Johnathon M; Lee, Nutishia; Perez-Cervantes, Carlos; Burnicka-Turek, Ozanna; Poss, Kenneth D.; Weber, Christopher R.; Laat, Wouter de; Ruthenburg, Alexander J.; Moskowitz, Ivan P.

doi:10.7554/elife.31683

Cited by 37 publications

(77 citation statements)

References 45 publications

(80 reference statements)

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“…RT-PCR experiments have shown that several eRNAs are intergenic chromatin enriched RNAs (icheRNA) [7]. Werner et al also showed that protein-coding genes proximal to icheRNA have higher expression levels than those near to other expressed lncRNA, suggesting that icheRNA could predict cis-gene transcription [4,5].…”

Section: Icherna Positively Correlate With Adjacent Genes In Expressionmentioning

confidence: 99%

“…Among these nuclear lncRNAs, chromatin-associated lncRNA (cheRNA) processes gene-regulatory roles [4][5][6]. In our recent studies, cheRNA promotes essential gene-enhancer contacts and is associated with transcript factor-dependent lncRNA [5,7]. However, a robust analytic pipeline for cheRNA as a group of functional nuclear RNAs has not been performed.…”

Section: Introductionmentioning

confidence: 99%

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Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

Sun

Wang

Perez-Cervantes

et al. 2019

Preprint

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Author SummaryChromatin-enriched nuclear RNA (cheRNA) is a class of gene regulatory non-coding RNAs.CheRNA provides a powerful way to profile the nuclear transcriptional landscape, especially to profile the noncoding transcriptome. The computational framework presented here provides a reliable approach to identifying cheRNA, and for studying cell-type specific gene regulation. We found that intergenic cheRNA, including intergenic cheRNA with high levels of H3K9me3 (a mark associated with closed/repressed chromatin), may act as a transcriptional activator. In contrast, antisense cheRNA, which originates from the complementary strand of the protein-coding gene, may interact with diverse chromatin modulators to repress local transcription. With our new pipeline, one future challenge will be refining the functional mechanisms of these noncoding RNA classes through exploring their regulatory roles, which are involved in diverse molecular and cellular processes in human and other organisms.

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Section: Icherna Positively Correlate With Adjacent Genes In Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

Sun

Wang

Perez-Cervantes

et al. 2019

Preprint

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“…A growing body of literature indicates that noncoding RNAs (ncRNAs) are transcribed from active CREs. The function of these transcripts and their role in gene regulation is an area of active research 1,7–10 . We previously demonstrated that differential enhancer transcription can be used to define a gene regulatory network (GRN) 1 .…”

Section: Introductionmentioning

confidence: 99%

“…The function of these transcripts and their role in gene regulation is an area of active research 1,7–10 . We previously demonstrated that differential enhancer transcription can be used to define a gene regulatory network (GRN) 1 . We identified ncRNAs whose expression was dependent on the cardiac transcription factor TBX5 1 .…”

Section: Introductionmentioning

confidence: 99%

“… Abstract Identification of the cis -regulatory elements (CREs) that regulate gene expression in specific cell types is critical for defining the gene regulatory networks (GRNs) that control normal physiology and disease states. We previously utilized non-coding RNA (ncRNA) profiling to define CREs that comprise a GRN in the adult mouse heart 1 . Here, we applied ncRNA profiling to the mouse retina in the presence and absence of Nrl , a rod photoreceptor-specific transcription factor required for rod versus cone photoreceptor cell fate.…”

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confidence: 99%

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Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Nadadur

Perez-Cervantes

Lonfat

et al. 2019

Preprint

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39Identification of the cis-regulatory elements (CREs) that regulate gene expression in 40 specific cell types is critical for defining the gene regulatory networks (GRNs) that 41 control normal physiology and disease states. We previously utilized non-coding RNA 42 (ncRNA) profiling to define CREs that comprise a GRN in the adult mouse heart 1 . Here, 43we applied ncRNA profiling to the mouse retina in the presence and absence of Nrl, a 44 rod photoreceptor-specific transcription factor required for rod versus cone 45 photoreceptor cell fate. Differential expression of Nrl-dependent ncRNAs positively 46 correlated with differential expression of Nrl-dependent local genes. Two distinct Nrl-47 dependent regulatory networks were discerned in parallel: Nrl-activated ncRNAs were 48 enriched for accessible chromatin in rods but not cones whereas Nrl-repressed ncRNAs 49were enriched for accessible chromatin in cones but not rods. Furthermore, differential 50Nrl-dependent ncRNA expression levels quantitatively correlated with photoreceptor cell 51 type-specific ATAC-seq read density. Direct assessment of Nrl-dependent ncRNA-52 defined loci identified functional cone photoreceptor CREs. This work supports 53 differential ncRNA profiling as a platform for identifying context-specific regulatory 54 elements and provides insight into the networks that define photoreceptor cell types. 55 contexts and its ability to distinguish activated and repressed elements has not been 79 examined. 80Here, we applied the differential ncRNA approach to identify regulatory elements 81 that are active in either of two specific cell types, rod and cone photoreceptors, in the 82 mouse retina. Rod photoreceptors are active in dim light and constitute the most 83 abundant retinal cell type, comprising ~80% of all mouse retinal cells and 95% of human 84 photoreceptors 11,12 . In contrast, cone photoreceptors are active in bright light and 85 mediate high-acuity vision and color vision. Their critical role in daylight vision makes 86 them a desirable cell type to replace from stem cells, or to target for gene therapy, in 87 diseases that lead to blindness 13 . An understanding of the GRNs that control cone 88 versus rod fate is essential for understanding both normal retinal biology and for cone 89 replacement, as has been recently demonstrated for rods in mice [14][15][16][17][18][19] . In addition, gene 90 therapy vectors that require expression specifically in rods and/or cones would benefit 91 from a broader range of validated photoreceptor CREs 20-22 . 92Rods and cones are produced by retinal progenitor cells (RPCs), with cones 93 generally produced earlier in development than rods, from RPCs that express the TFs 94Otx2, Olig2, and Oc1 23-26 . These and other TFs with essential roles in RPCs, rods, or 95 cones have been identified 27,28 . In addition to Otx2, a close homologue, Crx, is required 96 for normal gene expression in both rods and cones [29][30][31] . In contrast, Nrl, a basic leucine 97 zipper TF, is expressed only in rods and is ...

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Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation

Михайлов

Torrado

2018

J Mol Med

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There is growing evidence that putative gene regulatory networks including cardio-enriched transcription factors, such as PITX2, TBX5, ZFHX3, and SHOX2, and their effector/target genes along with downstream non-coding RNAs can play a potentially important role in the process of adaptive and maladaptive atrial rhythm remodeling. In turn, expression of atrial fibrillation-associated transcription factors is under the control of upstream regulatory non-coding RNAs. This review broadly explores gene regulatory mechanisms associated with susceptibility to atrial fibrillation-with key examples from both animal models and patients-within the context of both cardiac transcription factors and non-coding RNAs. These two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective control of atrial rhythm effector gene expression. Perturbations of a dynamic expression balance between transcription factors and corresponding non-coding RNAs can provoke the development or promote the progression of atrial fibrillation. We also outline deficiencies in current models and discuss ongoing studies to clarify remaining mechanistic questions. An understanding of the function of transcription factors and non-coding RNAs in gene regulatory networks associated with atrial fibrillation risk will enable the development of innovative therapeutic strategies.

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Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm

Cited by 37 publications

References 45 publications

Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation

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