Biology subjects

Lokhande, H.

Publications and source records attributed to Lokhande, H..

2 recordsLinked to original sources

bioRxiv2022

Epigenetic and Signaling Determinants of Blood-Brain Barrier-Regulatory Genetic Networks

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulators histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/{beta}-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

neuroscience↗

bioRxiv2021

Dissection of multiple sclerosis genetics identifies B and CD4 T cells as driver cell subsets

Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. We utilized chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We found that CD4 T and B cells were independently enriched for MS genetics and further refined the driver subsets to Th17 and memory B cells, respectively. We replicated our findings in data from untreated and treated MS patients and found that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominated numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.

genetics↗