scholarly journals A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease

2020 ◽  
Author(s):  
Sumantra Chatterjee ◽  
Kameko M Karasaki ◽  
Ashish Kapoor ◽  
Aravinda Chakravarti
Keyword(s):  
Gene Expression ◽  
Complex Disease ◽  
Disease Risk ◽  
Hirschsprung Disease ◽  
Kinase Gene ◽  
Risk Variants ◽  
Its Gene ◽  
Tyrosine Kinase Gene ◽  
Receptor Tyrosine Kinase Gene ◽  
Gene Regulatory

AbstractIn Hirschsprung disease (HSCR; congenital colonic aganglionosis), three GWAS-identified common variants residing in three distinct enhancers of the RET receptor tyrosine kinase gene reduce its gene expression and are causal disease risk variants. Further, their combined effects significantly dysregulate the expression of other functionally-related genes defining the RET gene regulatory network (GRN). In this study, we asked how many variants in how many distinct RET enhancers affect HSCR risk by reducing RET gene expression? We demonstrate that 22 additional HSCR-associated polymorphisms, both independent and associated, reside within multiple candidate RET enhancers and among which 7 display differential allelic enhancer activities. Of these 7 RET enhancers, two bind PAX3 and extend the known RET-EDNRB GRN. Therefore, sequence variants within a minimum of 10 RET enhancers affect HSCR risk, revealing a diverse regulatory code modulating complex disease risk even at a single locus.

scholarly journals A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease

2021 ◽  
Author(s):  
Sumantra Chatterjee ◽  
Kameko M. Karasaki ◽  
Lauren E. Fries ◽  
Ashish Kapoor ◽  
Aravinda Chakravarti
Keyword(s):  
Gene Expression ◽  
Disease Risk ◽  
Synergistic Effects ◽  
Single Gene ◽  
Hirschsprung Disease ◽  
Regulatory Elements ◽  
Kinase Gene ◽  
Enhancer Activity ◽  
Risk Variants

The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulatory elements (CREs) of the receptor tyrosine kinase gene RET, which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET–EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET–EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene.

scholarly journals Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B

2000 ◽  
Vol 67 (4) ◽  
pp. 822-831 ◽  
Author(s):  
Georg C. Schwabe ◽  
Sigrid Tinschert ◽  
Christian Buschow ◽  
Peter Meinecke ◽  
Gerhard Wolff ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Type B ◽  
Kinase Gene ◽  
Tyrosine Kinase Gene ◽  
Receptor Tyrosine Kinase Gene

FLT4 Receptor Tyrosine Kinase Gene Mapping to Chromosome Band 5q35 in Relation to the t(2;5), t(5;6), and t(3;5) Translocations

1993 ◽  
Vol 7 (3) ◽  
pp. 144-151 ◽  
Author(s):  
Elina Armstrong ◽  
Kumar Kastury ◽  
Olga Aprelikova ◽  
Florencia Bullrich ◽  
Christian Nezelof ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Gene Mapping ◽  
Receptor Tyrosine Kinase ◽  
Chromosome Band ◽  
Kinase Gene ◽  
Tyrosine Kinase Gene ◽  
Receptor Tyrosine Kinase Gene

scholarly journals Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

2019 ◽  
Author(s):  
Jing Yang ◽  
Amanda McGovern ◽  
Paul Martin ◽  
Kate Duffus ◽  
Xiangyu Ge ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Complex Disease ◽  
Target Genes ◽  
Disease Risk ◽  
Association Studies ◽  
Dna Interaction ◽  
Genome Wide Association Studies ◽  
Causal Genes

AbstractGenome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.

scholarly journals Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

2019 ◽  
Author(s):  
Jennifer K. Forsyth ◽  
Daniel Nachun ◽  
Michael J. Gandal ◽  
Daniel H. Geschwind ◽  
Ariana E. Anderson ◽  
...  
Keyword(s):  
Gene Networks ◽  
Disease Risk ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Protein Interaction Data ◽  
Regulatory Pathways ◽  
Polygenic Risk ◽  
Risk Variants ◽  
Gene Regulatory

AbstractBackground22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.MethodsUsing a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder.ResultsPolygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ- and ASD-associated neurodevelopmental networks, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation.ConclusionsThe current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD, and elucidate the mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.

scholarly journals Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

2020 ◽  
Author(s):  
James D. Hocker ◽  
Olivier B. Poirion ◽  
Fugui Zhu ◽  
Justin Buchanan ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Dependent Manner ◽  
Cardiac Cell ◽  
Risk Variants ◽  
Gene Regulatory

ABSTRACTBackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined.MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants.ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

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