Biology subjects

Sridhar Hannenhalli

Publications and source records attributed to Sridhar Hannenhalli.

4 recordsLinked to original sources

bioRxiv2016

A community overlap strategy reveals central genes and networks in heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvested 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtained genome-wide genotyping and gene expression measurements for a subset of 313. We built failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerged as a novel regulator whose network connectivity changed significantly between health and disease. Time-course RNA sequencing after PPP1R3A knock-down validated network-based predictions of metabolic pathway expression, increased cardiomyocyte size, and perturbed respiratory metabolism. Mice lacking PPP1R3A were protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify new cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a novel central protective regulator in heart failure.

Genomics↗

bioRxiv2015

A pathway-centric view of spatial proximity in the 3D nucleome across cell lines

Spatial organization of the genome is critical for condition-specific gene expression. Previous studies have shown that functionally related genes tend to be spatially proximal. However, these studies have not been extended to multiple human cell types, and the extent to which context-specific spatial proximity of a pathway is related to its context-specific activity is not known. We report the first pathway-centric analyses of spatial proximity in six human cell lines. We find that spatial proximity of genes in a pathway tends to be context-specific, in a manner consistent with the pathways context-specific expression and function; housekeeping genes are ubiquitously proximal to each other, and cancer-related pathways such as p53 signaling are uniquely proximal in hESC. Intriguingly, we find a correlation between the spatial proximity of genes and interactions of their protein products, even after accounting for the propensity of co-pathway proteins to interact. Related pathways are also often spatially proximal to one another, and housekeeping genes tend to be proximal to several other pathways suggesting their coordinating role. Further, the spatially proximal genes in a pathway tend to be the drivers of the pathway activity and are enriched for transcription, splicing and transport functions. Overall, our analyses reveal a pathway-centric organization of the 3D nucleome whereby functionally related and interacting genes, particularly the initial drivers of pathway activity, but also genes across multiple related pathways, are in spatial proximity in a context-specific way. Our results provide further insights into the role of differential spatial organization in cell type-specific pathway activity.

Bioinformatics↗

bioRxiv2015

Crowdsourcing: Spatial clustering of low-affinity binding sites amplifies in vivo transcription factor occupancy

To predict in vivo occupancy of a transcription factor (TF), current models consider only the immediate genomic context of a putative binding site (BS) - impact of the sites spatial chromatin context is not known. Using clusters of spatially proximal enhancers, or archipelagos, and DNase footprints to quantify TF occupancy, we report for the first time an emergent group-level effect on occupancy, whereby BS within an archipelago experience greater in vivo occupancy than comparable BS outside archipelagos, i.e. BS not in spatial proximity with other homotypic BS. This occupancy boost is tissue-specific and scales robustly with the total number of BS, or enhancers, for the TF in the archipelago. Interestingly, enhancers within an archipelago are non-uniformly impacted by the occupancy boost; specifically, archipelago enhancers that are enriched for BS corresponding to degenerate motifs exhibit the greatest occupancy boost, as well as the highest overall accessibility, evolutionary selection, and expression at neighboring gene loci. Strikingly, archipelago-wide activity scales with expression of TFs with degenerate, but not specific, motifs. We explain these results through biophysical modelling, which suggests that spatially proximal homotypic BS facilitate TF diffusion, and induce boosts in local TF concentration and occupancy. Together, we demonstrate for the first time cooperativity among genomically distal homotypic BS that is contingent upon their spatial proximity, consistent with a TF diffusion model. Through leveraging of three-dimensional chromatin structure and TF availability, weak archipelago binding sites crowdsource their occupancy as well as context specificity, with coordinated switch-like effect on overall archipelago activity.

Genomics↗

bioRxiv2015

First intron length in mammals is associated with 5′ exon skipping rate

The first introns in eukaryotes are much longer than downstream introns. While the functional roles of large first introns have been studied extensively, investigations into the mechanisms leading up to extreme lengths are limited. Prominently, Hong et al. noted that the first introns are predominantly in 5 UTR and suggested that its lengthening may have resulted from a 5-ward shifting of donor site due to a lower selection on splice site, as well as a selection to occlude upstream cryptic translation start sites. Here we suggest exon skipping as an alternative mechanism for first intron lengthening. Exon skipping results in consecutive introns becoming part of a single longer intron. We reasoned that a 5-biased exon skipping rate could lead to longer introns toward the 5-end of the gene, especially the first intron. Based on multiple datasets in human and mouse, we indeed found that internal exons toward the 5-end of the gene are skipped significantly more frequently than the downstream exons. Importantly, we show that 5-biased exon skipping is supported by consistent 5-bias in several genomic, epigenomic, contextual, and evolutionary features that can be functionally linked to exon skipping. Interestingly, we found that first introns are enriched for relics of, now defunct, exons, some of which may have been recruited for regulatory functions; a significantly greater-than-expected fraction of such exons are included in cDNAs in other mammals. Overall, our results offer 5-biased exon skipping as a novel, and arguably more potent, alternative explanation for substantially lengthening of first introns.

Genomics↗