Principles of regulatory information conservation between mouse and human

Cheng, Yong; Ma, Zhihai; Kim, Bong Hyun; Wu, Weisheng; Cayting, Philip; Boyle, Alan P.; Sundaram, Vasavi; Xing, Xiaoyun; Dogan, Nergiz; Li, Jingjing; Euskirchen, Ghia; Lin, Shin; Lin, Yiing; Visel, Axel; Kawli, Trupti; Yang, Xinqiong; Patacsil, Dorrelyn; Keller, Cheryl A.; Giardine, Belinda; Kundaje, Anshul; Wang, Ting; Pennacchio, Len A.; Weng, Zhiping; Hardison, Ross C.; Snyder, M

doi:10.1038/nature13985

Cited by 253 publications

(288 citation statements)

References 31 publications

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“…Regardless, we found that even those noncoding transcripts that are highly replicable are not conserved between mice and humans. When the biological function of lincRNAs can be found, they appear to be involved in regulation; our results are consistent with the idea that regulatory information in general, such as transcription factor binding, is highly diverged (22,23). Overall, our study demonstrates the extensive divergence in the expression of both noncoding genes as well as conserved, protein-coding genes that likely mediates the extensive differences between humans and mice.…”

Section: Histone Mark Differences For Differentially Expressed Genessupporting

confidence: 78%

Comparison of the transcriptional landscapes between human and mouse tissues

Lin

Nery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Although the similarities between humans and mice are typically highlighted, morphologically and genetically, there are many differences. To better understand these two species on a molecular level, we performed a comparison of the expression profiles of 15 tissues by deep RNA sequencing and examined the similarities and differences in the transcriptome for both protein-coding and -noncoding transcripts. Although commonalities are evident in the expression of tissue-specific genes between the two species, the expression for many sets of genes was found to be more similar in different tissues within the same species than between species. These findings were further corroborated by associated epigenetic histone mark analyses. We also find that many noncoding transcripts are expressed at a low level and are not detectable at appreciable levels across individuals. Moreover, the majority lack obvious sequence homologs between species, even when we restrict our attention to those which are most highly reproducible across biological replicates. Overall, our results indicate that there is considerable RNA expression diversity between humans and mice, well beyond what was described previously, likely reflecting the fundamental physiological differences between these two organisms.transcriptome | epigenome | species comparison | noncoding transcripts T he mouse has served as a valuable model organism for human biology and disease. It is widely assumed that biochemical, cellular, and developmental pathways in the mouse are highly conserved with humans and that many processes are clearly preserved at a molecular and genetic level. Moreover, recent detailed studies have examined gene expression in a limited number of tissues in humans and mice. These studies have indicated that gene expression is often conserved and is more similar between the comparable tissues of different organisms rather than within tissues of the same organism. In contrast, the transcript isoform repertoire was found to be markedly different between species (1, 2). Gene Expression Is More Similar Among Tissues Within a Species Than Between Corresponding Tissues of the Two SpeciesTo examine the similarities between humans and mice in much greater detail, we produced RNA-seq data from 13 human tissues [as part of the Encyclopedia Of DNA Elements (ENCODE)], another 11 human tissues [as part of the Roadmap Epigenomics Mapping Consortium (REMC) (3)], and 13 mouse tissues (for mouse ENCODE). We also included in our analysis other data from mouse ENCODE and the Illumina Human BodyMap 2.0 (HBM) (SI Materials and Methods). Sequencing was performed to a depth of 11,313,824-166,188,101 mappable reads (median of 68,399,538 with and an interquartile range of 31,557,836,199). In total, our analysis used 93 datasets encompassing the most tissue-diverse RNA-seq dataset to date spanning several major projects. Thirteen of the mouse and human orthologous datasets were produced by the same laboratory. For our analysis regarding noncoding transcripts, we incorporated an ad...

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Section: Histone Mark Differences For Differentially Expressed Genessupporting

confidence: 78%

Comparison of the transcriptional landscapes between human and mouse tissues

Lin

Nery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

330

297

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“…We first enumerated all CREs occupied by GATA1 in primary human EBs that are proximal to the ∼20 known pathogenic MED genes. Within these CREs, we identified 176 core GATA sites, and investigated the evolutionary conservation of these four nucleotides as a proxy for functionality (32,44,47,48). Surprisingly, although we observed only slight conservation for the GATA site within all ∼20,000 GATA1 chromatin occupancy sites across the genome, GATA sites within MED CREs were substantially conserved (Fig.…”

Section: Isogenic Cellular Models Phenocopy Cell-intrinsic Effects Ofmentioning

confidence: 95%

“…3D) (40). (9,44,47,48). This suggests the possibility that an important minority of causal genetic lesions may instead be located within NC regulatory regions.…”

Section: Isogenic Cellular Models Phenocopy Cell-intrinsic Effects Ofmentioning

confidence: 98%

Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

Wakabayashi

Ulirsch

Ludwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.GATA1 | cis-regulatory elements | noncoding mutations | Mendelian erythroid disorders W hole-exome sequencing (WES) and targeted sequencing approaches have greatly accelerated our ability to identify causal genetic lesions in both previously implicated and novel genes underlying monogenic disorders (1, 2). In hematology, WES has been extremely useful for identifying unknown genetic etiologies for various disorders, such as those affecting red blood cell (RBC) production, including Diamond-Blackfan anemia and congenital dyserythropoietic anemia (3-5), disorders of RBC structure and function (6, 7), and disorders affecting other aspects of hematologic function (2, 8). Despite this considerable success, however, more than 50% of cases of presumed monogenic diseases are refractory to current WES approaches (9). Although resolving these remaining cases will benefit from improvements in exome capture (10), read alignment (11), and variant annotation methodologies (11), the importance of genetic variation occurring within regulatory elements (REs) outside of the traditionally investigated coding sequences in hematologic and other diseases is being increasingly appreciated (12).Whole-genome sequencing (WGS) approaches are becoming progressively more available and affordable, but separating pathogenic genetic variation from benign or unrelated mutations remains especially difficult outside of protein-coding gen...

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“…10 Recent analysis of DNase I hypersensitive sites and occupancy profiles of transcription-factor binding in humans and mice suggests the preservation of similar regulatory mechanisms for adipose gene expression in both species, and this preservation could be leveraged to inform disease pathways. 23,24 We describe here the analysis of gene expression in 770 subcutaneous adipose samples from Metabolic Syndrome in Men (METSIM), a study of 10,197 men, 45-73 years of age, living in the Kuopio area of Finland. Study data include dense genotypes and extensive metabolic and cardiovascular traits, such as plasma lipids, inflammatory markers, glycemic traits, and anthropometric traits.…”

Section: Introductionmentioning

confidence: 99%

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Civelek

Pan

et al. 2017

The American Journal of Human Genetics

148

211

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Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 3 10 À8 ) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.

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Principles of regulatory information conservation between mouse and human

Cited by 253 publications

References 31 publications

Comparison of the transcriptional landscapes between human and mouse tissues

Comparison of the transcriptional landscapes between human and mouse tissues

Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

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