Architecture of the human regulatory network derived from ENCODE data

Gerstein, Mark; Kundaje, Anshul; Hariharan, Manoj; Landt, Stephen G.; Yan, Koon-Kiu; Cheng, Chao; Mu, Xinmeng Jasmine; Khurana, Ekta; Rozowsky, Joel; Alexander, Roger P.; Min, Renqiang; Alves, Pedro; Abyzov, Alexej; Addleman, Nick; Bhardwaj, Nitin; Boyle, Alan P.; Cayting, Philip; Charos, Alexandra; Chen, David Z.; Cheng, Yong; Clarke, Declan; Eastman, Catharine; Euskirchen, Ghia; Frietze, Seth; Fu, Yao; Gertz, Jason; Grubert, Fabian; Harmanci, Arif; Jain, Preti; Kasowski, Maya; Lacroute, Phil; Leng, Jing; Jin, Lian; Monahan, Hannah; O’Geen, Henriette; Ouyang, Zhengqing; Partridge, E. Christopher; Patacsil, Dorrelyn; Pauli, Florencia; Raha, Debasish; Ramı́rez, Lucı́a; Reddy, Timothy E.; Reed, Brian; Shi, Minyi; Slifer, Teri; Wang, Jing; Wu, Linfeng; Yang, Xinqiong; Yip, Kevin Y.; Zilberman-Schapira, Gili; Batzoglou, Serafim; Sidow, Arend; Farnham, Peggy J.; Myers, R; Weissman, Sherman M.; Snyder, M

doi:10.1038/nature11245

Cited by 1,365 publications

(1,373 citation statements)

References 48 publications

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“…We next examined the overlap of eSNPs with the transcription factor binding ChIP-seq data from ENCODE. [46][47][48] We found that eSNPs were statistically significantly enriched for transcription factor binding sites. Specifically, we found enrichment for CBX3, HDAC1, KDM5b, NRF1, IRF1, SIX5, and ZEB1 binding compared to 1,000 randomly generated SNP sets that were matched for frequency and distance ( Figure 2C).…”

Section: Validation and Replication Of Kidney Cis-eqtl Signalsmentioning

confidence: 84%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

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Section: Validation and Replication Of Kidney Cis-eqtl Signalsmentioning

confidence: 84%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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“…All three genes encode CFAPs and are specifically or preferentially expressed in the testis according to data from ENCODE, FANTOM, and GTEx. [36][37][38] Five CFAP43 mutations were identified in three MMAFaffected subjects (P003, P028, and P029) ( Figure 1 and Table 1). In subject P003 (II-1 in family 003 in Figure 1A), both CFAP43 mutations (GenBank: NM_025145.6) are nonsense: c.2802T>A (p.Cys934*) and c.4132C>T (p.Arg1378*).…”

Section: Resultsmentioning

confidence: 99%

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

226

200

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Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

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“…Based on the genomes of well-characterized model systems, multicellular organisms dedicate a significant portion of their protein coding genes (6-8%) to the expression of between 1000-2500 DNA-binding transcription factors 3 . With the exception of data from ENCODE and modENCODE projects [4][5][6][7] , in vivo genome-wide TF location data is available for relatively few TFs. To expand this analysis for a wider range of organisms, scalable methods are needed for the low-cost and high-throughput examination of thousands of TFs.…”

Section: Introductionmentioning

confidence: 99%

Mapping genome-wide transcription-factor binding sites using DAP-seq

Bartlett¹,

O’Malley²,

Huang³

et al. 2017

Nat Protoc

349

250

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In order to enable low-cost, high-throughput generation of cistrome and epicistrome maps for any organism, we developed DNA affinity purification sequencing (DAP-seq), a transcription factor (TF) binding site discovery assay that couples affinity-purified TFs with next-generation sequencing of a genomic DNA library. The method is fast, inexpensive, and more easily scaled than ChIP-seq. DNA libraries are constructed using native genomic DNA from any source of interest, preserving cell-and tissue-specific chemical modifications that are known to impact TF binding (such as DNA methylation) and providing increased specificity compared to in silico motif prediction methods such as protein binding microarrays (PBM) and systematic evolution of ligands by exponential enrichment (SELEX). The resulting DNA library is incubated with an affinity-tagged in vitro expressed TF, and TF-DNA complexes are purified using magnetic separation of the affinity tag. Bound genomic DNA is eluted from the TF and sequenced using next-generation sequencing. Sequence reads are mapped to a reference genome, identifying genome-wide binding locations for each TF assayed, from which sequence motifs can then be

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Architecture of the human regulatory network derived from ENCODE data

Cited by 1,365 publications

References 48 publications

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Mapping genome-wide transcription-factor binding sites using DAP-seq

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