Dataset Information

PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.

ABSTRACT:

Background

Genome-wide comparisons of transcription factor binding sites in different species can be used to evaluate evolutionary constraints that shape gene regulatory circuits and to understand how the interaction between transcription factors shapes their binding landscapes over evolution.

Results

We have compared the PPARG binding landscapes in macrophages to investigate the evolutionary impact on PPARG binding diversity in mouse and humans for this important nuclear receptor. Of note, only 5% of the PPARG binding sites were shared between the two species. In contrast, at the gene level, PPARG target genes conserved between both species constitute more than 30% of the target genes regulated by PPARG ligand in human macrophages. Moreover, the majority of all PPARG binding sites (55-60%) in macrophages show co-occupancy of the lineage-specification factor PU.1 in both species. Exploring the evolutionary dynamics of PPARG binding sites, we observed that PU.1 co-binding to PPARG sites appears to be important for possible PPARG ancestral functions such as lipid metabolism. Thus we speculate that PU.1 may have guided utilization of these species-specific PPARG conserved binding sites in macrophages during evolution.

Conclusions

We propose a model in which PU.1 sites may have served as "anchor" loci for the formation of new and functionally relevant PPARG binding sites throughout evolution. As PU.1 is an essential factor in macrophage biology, such an evolutionary mechanism would allow for the establishment of relevant PPARG regulatory modules in a PU.1-dependent manner and yet permit for nuanced regulatory changes in individual species.

SUBMITTER: Pott S

PROVIDER: S-EPMC3485280 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.

Pott Sebastian S Kamrani Nima K NK Bourque Guillaume G Pettersson Sven S Liu Edison T ET

PloS one 20121031 10

<h4>Background</h4>Genome-wide comparisons of transcription factor binding sites in different species can be used to evaluate evolutionary constraints that shape gene regulatory circuits and to understand how the interaction between transcription factors shapes their binding landscapes over evolution.<h4>Results</h4>We have compared the PPARG binding landscapes in macrophages to investigate the evolutionary impact on PPARG binding diversity in mouse and humans for this important nuclear receptor ...[more]

PMID: 23118933

Similar Datasets

Project description:Transposon insertion sequencing (TIS; also known as TnSeq) is a potent approach commonly used to comprehensively define the genetic loci that contribute to bacterial fitness in diverse environments. A key presumption underlying analyses of TIS datasets is that loci with a low frequency of transposon insertions contribute to fitness. However, it is not known whether factors such as nucleoid binding proteins can alter the frequency of transposon insertion and thus whether TIS output may systematically reflect factors that are independent of the role of the loci in fitness. Here, we investigated whether the histone-like nucleoid structuring (H-NS) protein, which preferentially associates with AT-rich sequences, modulates the frequency of Mariner transposon insertion in the Vibrio cholerae genome, using comparative analysis of TIS results from wild-type (wt) and Δhns V. cholerae strains. These analyses were overlaid on gene classification based on GC content as well as on extant genome-wide identification of H-NS binding loci. Our analyses revealed a significant dearth of insertions within AT-rich loci in wt V. cholerae that was not apparent in the Δhns insertion library. Additionally, we observed a striking correlation between genetic loci that are overrepresented in the Δhns insertion library relative to their insertion frequency in wt V. cholerae and loci previously found to physically interact with H-NS. Collectively, our findings reveal that factors other than genetic fitness can systematically modulate the frequency of transposon insertions in TIS studies and add a cautionary note to interpretation of TIS data, particularly for AT-rich sequences. Transposon insertion sequencing (TIS) is often used to assess the relative frequency with which genetic loci can be disrupted, which is taken as an indicator of their importance for bacterial fitness. Here, we report that biological factors other than the relative levels of fitness of insertion mutants can influence TIS output. We found that the presence of the DNA binding protein H-NS, which preferentially recognizes AT-rich sequences, is linked to significant underrepresentation of mutations within AT-rich loci in transposon insertion libraries. Furthermore, there is a marked correspondence between loci bound by H-NS and loci with an increased frequency of disruption in a Δhns insertion library relative to a wt library. Our data suggest that factors other than genetic fitness (e.g., DNA binding proteins such as H-NS) can systematically modulate the frequency of transposon insertions in TIS studies and add a note of caution for interpretation of TIS data.

Dataset Information

PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.

Background

Results

Conclusions

Publications

PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets