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Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution.

ABSTRACT: BACKGROUND:Because species-specific gene expression is driven by species-specific regulation, understanding the relationship between sequence and function of the regulatory regions in different species will help elucidate how differences among species arise. Despite active experimental and computational research, relationships among sequence, conservation, and function are still poorly understood. RESULTS:We compared transcription factor occupied segments (TFos) for 116 human and 35 mouse TFs in 546 human and 125 mouse cell types and tissues from the Human and the Mouse ENCODE projects. We based the map between human and mouse TFos on a one-to-one nucleotide cross-species mapper, bnMapper, that utilizes whole genome alignments (WGA). Our analysis shows that TFos are under evolutionary constraint, but a substantial portion (25.1% of mouse and 25.85% of human on average) of the TFos does not have a homologous sequence on the other species; this portion varies among cell types and TFs. Furthermore, 47.67% and 57.01% of the homologous TFos sequence shows binding activity on the other species for human and mouse respectively. However, 79.87% and 69.22% is repurposed such that it binds the same TF in different cells or different TFs in the same cells. Remarkably, within the set of repurposed TFos, the corresponding genome regions in the other species are preferred locations of novel TFos. These events suggest exaptation of some functional regulatory sequences into new function. Despite TFos repurposing, we did not find substantial changes in their predicted target genes, suggesting that CRMs buffer evolutionary events allowing little or no change in the TFos - target gene associations. Thus, the small portion of TFos with strictly conserved occupancy underestimates the degree of conservation of regulatory interactions. CONCLUSION:We mapped regulatory sequences from an extensive number of TFs and cell types between human and mouse using WGA. A comparative analysis of this correspondence unveiled the extent of the shared regulatory sequence across TFs and cell types under study. Importantly, a large part of the shared regulatory sequence is repurposed on the other species. This sequence, fueled by turnover events, provides a strong case for exaptation in regulatory elements.

SUBMITTER: Denas O

PROVIDER: S-EPMC4333152 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution.

Denas Olgert O Sandstrom Richard R Cheng Yong Y Beal Kathryn K Herrero Javier J Hardison Ross C RC Taylor James J

BMC genomics 20150214

<h4>Background</h4>Because species-specific gene expression is driven by species-specific regulation, understanding the relationship between sequence and function of the regulatory regions in different species will help elucidate how differences among species arise. Despite active experimental and computational research, relationships among sequence, conservation, and function are still poorly understood.<h4>Results</h4>We compared transcription factor occupied segments (TFos) for 116 human and ...[more]

PMID: 25765714

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Project description:BACKGROUND: Pre-implantation development is a crucial step in successful implantation and pregnancy in mammals. It has been studied in depth, but mostly in laboratory animal models. Less is known about the regulatory mechanism involved in the pre-implantation development in humans and about the comparative aspects. METHODS: Here, we employed the microarray datasets from the public database library of GEO and applied comparative analysis of genome wide temporal gene expression data based on statistical analysis and functional annotation for both mouse and human, demonstrating the discordance between the regulatory mechanisms of both mouse and human pre-implantation development. RESULTS: There were differences between mouse and human pre-implantation development both in the global gene expression pattern and in the expression changes of individual genes at each stage, including different major transient waves of transcription profiles and some stage-specific genes and significantly related pathways. There also appeared to be different functional changes from one stage to another between mouse and human. CONCLUSIONS: The analysis presented here lead to interesting and complementary conclusions that the regulatory mechanism of human pre-implantation development is not completely the same as the mouse. Not as the fact that 1-cell to 2-cell stage is important for mouse pre-implantation development, the 4-cell stage and 8-cell stage are both essential for human. Unlike in mouse, of which most of pathways found were related to energy, RNA and protein metabolism, the identified pathways in human were mostly disease-related and associated with human pre-implantation embryonic development. All of these suggest that a further comparative analysis should be required for applying the result of mouse expression data to human research or therapy, particularly in pre-implantation developments. Our study provides several potential targets of genes and pathways for studying the regulatory mechanism of human pre-implantation development using mouse model.

Dataset Information

Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution.

Publications

Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution.

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