Daniel Richard

All Publications

• Lineage-specific differences and regulatory networks governing human chondrocyte development ELIFE Richard, D., Pregizer, S., Venkatasubramanian, D., Raftery, R. M., Muthuirulan, P., Liu, Z., Capellini, T. D., Craft, A. M. 2023; 12

  Abstract

  To address large gaps in our understanding of the molecular regulation of articular and growth plate cartilage development in humans, we used our directed differentiation approach to generate these distinct cartilage tissues from human embryonic stem cells. The resulting transcriptomic profiles of hESC-derived articular and growth plate chondrocytes were similar to fetal epiphyseal and growth plate chondrocytes, with respect to genes both known and previously unknown to cartilage biology. With the goal to characterize the regulatory landscapes accompanying these respective transcriptomes, we mapped chromatin accessibility in hESC-derived chondrocyte lineages, and mouse embryonic chondrocytes, using ATAC-sequencing. Integration of the expression dataset with the differentially accessible genomic regions revealed lineage-specific gene regulatory networks. We validated functional interactions of two transcription factors (TFs) (RUNX2 in growth plate chondrocytes and RELA in articular chondrocytes) with their predicted genomic targets. The maps we provide thus represent a framework for probing regulatory interactions governing chondrocyte differentiation. This work constitutes a substantial step towards comprehensive and comparative molecular characterizations of distinct chondrogenic lineages and sheds new light on human cartilage development and biology.

  View details for DOI 10.7554/eLife.79925

  View details for Web of Science ID 000964336400001

  View details for PubMedID 36920035

  View details for PubMedCentralID PMC10069868

• Regulatory dissection of the severe COVID-19 risk locus introgressed by Neanderthals ELIFE Jagoda, E., Marnetto, D., Senevirathne, G., Gonzalez, V., Baid, K., Montinaro, F., Richard, D., Falzarano, D., LeBlanc, E., Colpitts, C. C., Banerjee, A., Pagani, L., Capellini, T. D. 2023; 12

  Abstract

  Individuals infected with the SARS-CoV-2 virus present with a wide variety of symptoms ranging from asymptomatic to severe and even lethal outcomes. Past research has revealed a genetic haplotype on chromosome 3 that entered the human population via introgression from Neanderthals as the strongest genetic risk factor for the severe response to COVID-19. However, the specific variants along this introgressed haplotype that contribute to this risk and the biological mechanisms that are involved remain unclear. Here, we assess the variants present on the risk haplotype for their likelihood of driving the genetic predisposition to severe COVID-19 outcomes. We do this by first exploring their impact on the regulation of genes involved in COVID-19 infection using a variety of population genetics and functional genomics tools. We then perform a locus-specific massively parallel reporter assay to individually assess the regulatory potential of each allele on the haplotype in a multipotent immune-related cell line. We ultimately reduce the set of over 600 linked genetic variants to identify four introgressed alleles that are strong functional candidates for driving the association between this locus and severe COVID-19. Using reporter assays in the presence/absence of SARS-CoV-2, we find evidence that these variants respond to viral infection. These variants likely drive the locus' impact on severity by modulating the regulation of two critical chemokine receptor genes: CCR1 and CCR5. These alleles are ideal targets for future functional investigations into the interaction between host genomics and COVID-19 outcomes.

  View details for DOI 10.7554/eLife.71235

  View details for Web of Science ID 000932804200001

  View details for PubMedID 36763080

  View details for PubMedCentralID PMC9917435