Dataset Information

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.

ABSTRACT: As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.

SUBMITTER: Ballester B

PROVIDER: S-EPMC4359374 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.

Ballester Benoit B Medina-Rivera Alejandra A Schmidt Dominic D Gonzàlez-Porta Mar M Carlucci Matthew M Chen Xiaoting X Chessman Kyle K Faure Andre J AJ Funnell Alister P W AP Goncalves Angela A Kutter Claudia C Lukk Margus M Menon Suraj S McLaren William M WM Stefflova Klara K Watt Stephen S Weirauch Matthew T MT Crossley Merlin M Marioni John C JC Odom Duncan T DT Flicek Paul P Wilson Michael D MD

eLife 20141003

As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs wer ...[more]

PMID: 25279814

Similar Datasets

Project description:BACKGROUND:Identifying DNA sequences (enhancers) that direct the precise spatial and temporal expression of developmental control genes remains a significant challenge in the annotation of vertebrate genomes. Locating these sequences, which in many cases lie at a great distance from the transcription start site, has been a major obstacle in deciphering gene regulation. Coupling of comparative genomics with functional validation to locate such regulatory elements has been a successful method in locating many such regulatory elements. But most of these studies looked either at a single gene only or the whole genome without focusing on any particular process. The pressing need is to integrate the tools of comparative genomics with knowledge of developmental biology to validate enhancers for developmental transcription factors in greater detail RESULTS:Our results show that near four different genes (nkx3.2, pax9, otx1b and foxa2) in zebrafish, only 20-30% of highly conserved DNA sequences can act as developmental enhancers irrespective of the tissue the gene expresses in. We find that some genes also have multiple conserved enhancers expressing in the same tissue at the same or different time points in development. We also located non-conserved enhancers for two of the genes (pax9 and otx1b). Our modified Bacterial artificial chromosome (BACs) studies for these 4 genes revealed that many of these enhancers work in a synergistic fashion, which cannot be captured by individual DNA constructs and are not conserved at the sequence level. Our detailed biochemical and transgenic analysis revealed Foxa1 binds to the otx1b non-conserved enhancer to direct its activity in forebrain and otic vesicle of zebrafish at 24 hpf. CONCLUSION:Our results clearly indicate that high level of functional conservation of genes is not necessarily associated with sequence conservation of its regulatory elements. Moreover certain non conserved DNA elements might have role in gene regulation. The need is to bring together multiple approaches to bear upon individual genes to decipher all its regulatory elements.

Project description:BACKGROUND:Spermatozoa have a remarkable epigenome in line with their degree of specialization, their unique nature and different requirements for successful fertilization. Accordingly, perturbations in the establishment of DNA methylation patterns during male germ cell differentiation have been associated with infertility in several species. While bull semen is widely used in artificial insemination, the literature describing DNA methylation in bull spermatozoa is still scarce. The purpose of this study was therefore to characterize the bull sperm methylome relative to both bovine somatic cells and the sperm of other mammals through a multiscale analysis. RESULTS:The quantification of DNA methylation at CCGG sites using luminometric methylation assay (LUMA) highlighted the undermethylation of bull sperm compared to the sperm of rams, stallions, mice, goats and men. Total blood cells displayed a similarly high level of methylation in bulls and rams, suggesting that undermethylation of the bovine genome was specific to sperm. Annotation of CCGG sites in different species revealed no striking bias in the distribution of genome features targeted by LUMA that could explain undermethylation of bull sperm. To map DNA methylation at a genome-wide scale, bull sperm was compared with bovine liver, fibroblasts and monocytes using reduced representation bisulfite sequencing (RRBS) and immunoprecipitation of methylated DNA followed by microarray hybridization (MeDIP-chip). These two methods exhibited differences in terms of genome coverage, and consistently, two independent sets of sequences differentially methylated in sperm and somatic cells were identified for RRBS and MeDIP-chip. Remarkably, in the two sets most of the differentially methylated sequences were hypomethylated in sperm. In agreement with previous studies in other species, the sequences that were specifically hypomethylated in bull sperm targeted processes relevant to the germline differentiation program (piRNA metabolism, meiosis, spermatogenesis) and sperm functions (cell adhesion, fertilization), as well as satellites and rDNA repeats. CONCLUSIONS:These results highlight the undermethylation of bull spermatozoa when compared with both bovine somatic cells and the sperm of other mammals, and raise questions regarding the dynamics of DNA methylation in bovine male germline. Whether sperm undermethylation has potential interactions with structural variation in the cattle genome may deserve further attention.

Project description:BackgroundConsistent individual differences in behaviour, known as animal personalities, have been demonstrated within and across species. In fish, studies applying an animal personality approach have been used to resolve variation in physiological and molecular data suggesting a linkage, genotype-phenotype, between behaviour and transcriptome regulation. In this study, using three fish species (zebrafish; Danio rerio, Atlantic salmon; Salmo salar and European sea bass; Dicentrarchus labrax), we firstly address whether personality-specific mRNA transcript abundances are transferrable across distantly-related fish species and secondly whether a proactive transcriptome signature is conserved across all three species.ResultsPrevious zebrafish transcriptome data was used as a foundation to produce a curated list of mRNA transcripts related to animal personality across all three species. mRNA transcript copy numbers for selected gene targets show that differential mRNA transcript abundance in the brain appears to be partially conserved across species relative to personality type. Secondly, we performed RNA-Seq using whole brains from S. salar and D. labrax scoring positively for both behavioural and molecular assays for proactive behaviour. We further enriched this dataset by incorporating a zebrafish brain transcriptome dataset specific to the proactive phenotype. Our results indicate that cross-species molecular signatures related to proactive behaviour are functionally conserved where shared functional pathways suggest that evolutionary convergence may be more important than individual mRNAs.ConclusionsOur data supports the proposition that highly polygenic clusters of genes, with small additive effects, likely support the underpinning molecular variation related to the animal personalities in the fish used in this study. The polygenic nature of the proactive brain transcriptome across all three species questions the existence of specific molecular signatures for proactive behaviour, at least at the granularity of specific regulatory gene modules, level of genes, gene networks and molecular functions.

Project description:BackgroundAnimal's efficiency in converting feed into lean gain is a critical issue for the profitability of meat industries. This study aimed to describe shared and specific molecular responses in different tissues of pigs divergently selected over eight generations for residual feed intake (RFI).ResultsPigs from the low RFI line had an improved gain-to-feed ratio during the test period and displayed higher leanness but similar adiposity when compared with pigs from the high RFI line at 132 days of age. Transcriptomics data were generated from longissimus muscle, liver and two adipose tissues using a porcine microarray and analyzed for the line effect (n = 24 pigs per line). The most apparent effect of the line was seen in muscle, whereas subcutaneous adipose tissue was the less affected tissue. Molecular data were analyzed by bioinformatics and subjected to multidimensional statistics to identify common biological processes across tissues and key genes participating to differences in the genetics of feed efficiency. Immune response, response to oxidative stress and protein metabolism were the main biological pathways shared by the four tissues that distinguished pigs from the low or high RFI lines. Many immune genes were under-expressed in the four tissues of the most efficient pigs. The main genes contributing to difference between pigs from the low vs high RFI lines were CD40, CTSC and NTN1. Different genes associated with energy use were modulated in a tissue-specific manner between the two lines. The gene expression program related to glycogen utilization was specifically up-regulated in muscle of pigs from the low RFI line (more efficient). Genes involved in fatty acid oxidation were down-regulated in muscle but were promoted in adipose tissues of the same pigs when compared with pigs from the high RFI line (less efficient). This underlined opposite line-associated strategies for energy use in skeletal muscle and adipose tissue. Genes related to cholesterol synthesis and efflux in liver and perirenal fat were also differentially regulated in pigs from the low vs high RFI lines.ConclusionsNon-productive functions such as immunity, defense against pathogens and oxidative stress contribute likely to inter-individual variations in feed efficiency.

Dataset Information

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.

Publications

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure