Biology subjects

Chandra, V.

Publications and source records attributed to Chandra, V..

4 recordsLinked to original sources

bioRxiv2018

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) enriched in Western Finland protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, especially compared with individuals matched for the genotype of a common T2D risk variant in SLC30A8, p.Arg325. In genome-edited human IPS-derived {beta}-like cells, we establish that the p.Arg138* variant results in reduced SLC30A8 expression due to haploinsufficiency. In human {beta}-cells loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function, which was also seen in isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aiming at maintaining insulin secretion capacity in T2D.

genetics↗

bioRxiv2018

FitHiChIP: Identification of significant chromatin contacts from HiChIP data

Here we describe FitHiChIP (github.com/ay-lab/FitHiChIP), a computational method for identifying chromatin contacts among regulatory regions such as en-hancers and promoters from HiChIP/PLAC-seq data. FitHiChIP jointly models the non-uniform coverage and genomic distance scaling of HiChIP data, captures previously validated enhancer interactions for several genes including MYC and TP53, and recovers contacts genome-wide that are supported by ChIA-PET, pro-moter capture Hi-C and Hi-C data. FitHiChIP also provides a framework for differential contact analysis as showcased in a comparison of HiChIP data we have generated for two distinct immune cell types.

bioinformatics↗

bioRxiv2018

An inter-chromosomal transcription hub activates the unfolded protein response in plasma cells

Previous studies have indicated that the transcription signature of antibody-secreting cells is closely associated with the induction of the unfolded protein response pathway (UPR). Here we have used genome-wide and single cell analyses to examine the folding patterns of plasma cell genomes. We found that plasma cells adopt a cartwheel configuration and undergo large-scale changes in chromatin folding at genomic regions associated with a plasma cell specific transcription signature. During plasma cell differentiation, Blimp1 assembles into an inter-chromosomal transcription hub with genes associated with the UPR, biosynthesis of the endoplasmic reticulum (ER) as well as a cluster of genes linked with Alzheimers disease. We suggest that the assembly of the Blimp1-UPR-ER transcription hub permits the coordinate activation of a wide spectrum of genes that collectively establish plasma cell identity.

immunology↗

bioRxiv2017

Comprehensive characterization of neutrophil genome topology

Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains. However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple topologically associating domains. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named super-contraction. Super-contraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Super-contraction was accompanied by the repositioning of centromeres, pericentromeres and Long-Interspersed Nuclear Elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin-B Receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mini-nucleoli to the lamina: a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving super-contraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitate the folding of the neutrophil genome into a confined geometry imposed by a multi-lobed nuclear architecture.

molecular biology↗