Female‐specific gene regulation in malaria parasites by an AP2‐family transcription factor

Abstract The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

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Identification of MEF2-regulated genes during muscle differentiation

Physiological Genomics ◽

10.1152/physiolgenomics.00149.2004 ◽

2004 ◽

Vol 20 (1) ◽

pp. 143-151 ◽

Cited By ~ 19

Author(s):

James Paris ◽

Carl Virtanen ◽

Zhibin Lu ◽

Mark Takahashi

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Transcription Factors ◽

Neuromuscular Junctions ◽

Muscle Differentiation ◽

Signaling Cascades ◽

Specific Gene ◽

Genetic Mechanisms ◽

Selection Parameters ◽

First Time

Although a great deal has been elucidated concerning the mechanisms regulating muscle differentiation, little is known about transcription factor-specific gene regulation. Our understanding of the genetic mechanisms regulating cell differentiation is quite limited. Much of what has been defined centers on regulatory signaling cascades and transcription factors. Surprisingly few studies have investigated the association of genes with specific transcription factors. To address these issues, we have utilized a method coupling chromatin immunoprecipitation and CpG microarrays to characterize the genes associated with MEF2 in differentiating C2C12 cells. Results demonstrated a defined binding pattern over the course of differentiation. Filtered data demonstrated 9 clones to be elevated at 0 h, 792 at 6 h, 163 by 1 day, and 316 at 3 days. Using unbiased selection parameters, we selected a subset of 291 prospective candidates. Clones were sequenced and filtered for removal of redundancy between clones and for the presence of repetitive elements. We were able to place 50 of these on the mouse genome, and 20 were found to be located near well-annotated genes. From this list, previously undefined associations with MEF2 were discovered. Many of these genes represent proteins involved in neurogenesis, neuromuscular junctions, signaling and metabolism. The remaining clones include many full-length cDNA and represent novel gene targets. The results of this study provides for the first time, a unique look at gene regulation at the level of transcription factor binding in differentiating muscle.

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ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function

Circulation Research ◽

10.1161/circresaha.120.317145 ◽

2020 ◽

Vol 127 (12) ◽

pp. 1502-1518

Author(s):

Giselle Galang ◽

Ravi Mandla ◽

Hongmei Ruan ◽

Catherine Jung ◽

Tanvi Sinha ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transcription Factor ◽

Sinoatrial Node ◽

Regulatory Elements ◽

Right Atrial ◽

Specific Gene ◽

Human Populations ◽

And Function ◽

Accessible Chromatin

Rationale: Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) have a distinct gene expression program that allows them to fire automatically and initiate the heartbeat. Although critical SAN transcription factors, including Isl1 (Islet-1), Tbx3 (T-box transcription factor 3), and Shox2 (short-stature homeobox protein 2), have been identified, the cis -regulatory architecture that governs PC-specific gene expression is not understood, and discrete enhancers required for gene regulation in the SAN have not been identified. Objective: To define the epigenetic profile of PCs using comparative ATAC-seq (assay for transposase-accessible chromatin with sequencing) and to identify novel enhancers involved in SAN gene regulation, development, and function. Methods and Results: We used ATAC-seq on sorted neonatal mouse SAN to compare regions of accessible chromatin in PCs and right atrial cardiomyocytes. PC-enriched assay for transposase-accessible chromatin peaks, representing candidate SAN regulatory elements, were located near established SAN genes and were enriched for distinct sets of TF (transcription factor) binding sites. Among several novel SAN enhancers that were experimentally validated using transgenic mice, we identified a 2.9-kb regulatory element at the Isl1 locus that was active specifically in the cardiac inflow at embryonic day 8.5 and throughout later SAN development and maturation. Deletion of this enhancer from the genome of mice resulted in SAN hypoplasia and sinus arrhythmias. The mouse SAN enhancer also directed reporter activity to the inflow tract in developing zebrafish hearts, demonstrating deep conservation of its upstream regulatory network. Finally, single nucleotide polymorphisms in the human genome that occur near the region syntenic to the mouse enhancer exhibit significant associations with resting heart rate in human populations. Conclusions: (1) PCs have distinct regions of accessible chromatin that correlate with their gene expression profile and contain novel SAN enhancers, (2) cis -regulation of Isl1 specifically in the SAN depends upon a conserved SAN enhancer that regulates PC development and SAN function, and (3) a corresponding human ISL1 enhancer may regulate human SAN function.

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Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites

10.1101/2020.10.15.340877 ◽

2020 ◽

Cited By ~ 1

Author(s):

Marina Borschiwer ◽

Melissa Bothe ◽

Gözde Kibar ◽

Alisa Fuchs ◽

Stefanie Schöne ◽

...

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Dna Binding ◽

Receptor Binding ◽

Binding Sites ◽

Specific Gene ◽

Functional Diversification ◽

Enhancer Activity ◽

Sequence Composition

AbstractThe glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied AR and GR in an equivalent cellular context. Analysis of chromatin and sequence features suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the results of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in selectively guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared between AR and GR shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, we find that shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

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Faculty Opinions recommendation of Nucleosome-driven transcription factor binding and gene regulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717970656.793469107 ◽

2013 ◽

Author(s):

Cheng-Ming Chiang

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Transcription Factor Binding ◽

Factor Binding

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A unique histone 3 lysine 14 chromatin signature underlies tissue-specific gene regulation

Molecular Cell ◽

10.1016/j.molcel.2021.01.041 ◽

2021 ◽

Author(s):

Isabel Regadas ◽

Olle Dahlberg ◽

Roshan Vaid ◽

Oanh Ho ◽

Sergey Belikov ◽

...

Keyword(s):

Gene Regulation ◽

Specific Gene ◽

Chromatin Signature ◽

Tissue Specific ◽

Tissue Specific Gene ◽

Histone 3

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Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

Genome Biology ◽

10.1186/s13059-021-02325-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Tejaswi Iyyanki ◽

Baozhen Zhang ◽

Qixuan Wang ◽

Ye Hou ◽

Qiushi Jin ◽

...

Keyword(s):

Bladder Cancer ◽

Transcription Factor ◽

Cancer Cell ◽

Genome Structure ◽

Transcription Factor Binding ◽

Specific Gene ◽

Open Chromatin ◽

Factor Binding ◽

3D Genome ◽

Genome Wide

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

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