Daniel Richard

All Publications

• Functional genomics of human skeletal development and the patterning of height heritability CELL Richard, D., Muthuirulan, P., Young, M., Yengo, L., Vedantam, S., Marouli, E., Bartell, E., GIANT Consortium, G. T., Hirschhorn, J., Capellini, T. D. 2025; 188 (1): 15-32.e24

  Abstract

  Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development. Next, using these maps in tandem with height genome-wide association study (GWAS) signals, we disentangle the regulatory impacts that skeletal element-specific versus global-acting variants have on skeletal growth, revealing the prime importance of regulatory pleiotropy in controlling height variation. Finally, as height is highly heritable, and thus often the test case for complex-trait genetics, we leverage these datasets within a testable omnigenic model framework to discover novel chondrocyte developmental modules and peripheral-acting factors shaping height biology and skeletal growth.

  View details for DOI 10.1016/j.cell.2024.10.040

  View details for Web of Science ID 001412813600001

  View details for PubMedID 39549696

  View details for PubMedCentralID PMC11724752

• Disagreement on foundational principles of biological aging. PNAS nexus Gladyshev, V. N., Anderson, B., Barlit, H., Barré, B., Beck, S., Behrouz, B., Belsky, D. W., Chaix, A., Chamoli, M., Chen, B. H., Cheng, K., Chuprin, J., Churchill, G. A., Cipriano, A., Colville, A., Deelen, J., Deigin, Y., Edmonds, K. K., English, B. W., Fang, R., Florea, M., Gershteyn, I. M., Gill, D., Goetz, L. H., Gorbunova, V., Griffin, P. T., Horvath, S., Borch Jensen, M., Jin, X., Jovanovska, S., Kajderowicz, K. M., Kasahara, T., Kerepesi, C., Kulkarni, S., Labunskyy, V. M., Levine, M. E., Libert, S., Lu, J. Y., Lu, Y. R., Marioni, R. E., McCoy, B. M., Mitchell, W., Moqri, M., Nasirian, F., Niimi, P., Oh, H. S., Okundaye, B., Parkhitko, A. A., Peshkin, L., Petljak, M., Poganik, J. R., Pridham, G., Promislow, D. E., Prusisz, W., Quiniou, M., Raj, K., Richard, D., Ricon, J. L., Rutledge, J., Scheibye-Knudsen, M., Schork, N. J., Seluanov, A., Shadpour, M., Shindyapina, A. V., Shuken, S. R., Sivakumar, S., Stoeger, T., Sugiura, A., Sutton, N. R., Suvorov, A., Tarkhov, A. E., Teeling, E. C., Trapp, A., Tyshkovskiy, A., Unfried, M., Ward-Caviness, C. K., Yim, S. H., Ying, K., Yunes, J., Zhang, B., Zhavoronkov, A. 2024; 3 (12): pgae499

  Abstract

  To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

  View details for DOI 10.1093/pnasnexus/pgae499

  View details for PubMedID 39660064

  View details for PubMedCentralID PMC11630784

• 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

• Joint disease-specificity at the regulatory base-pair level NATURE COMMUNICATIONS Muthuirulan, P., Zhao, D., Young, M., Richard, D., Liu, Z., Emami, A., Portilla, G., Hosseinzadeh, S., Cao, J., Maridas, D., Sedlak, M., Menghini, D., Cheng, L., Li, L., Ding, X., Ding, Y., Rosen, V., Kiapour, A. M., Capellini, T. D. 2021; 12 (1): 4161

  Abstract

  Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

  View details for DOI 10.1038/s41467-021-24345-9

  View details for Web of Science ID 000672715200007

  View details for PubMedID 34230488

  View details for PubMedCentralID PMC8260791

• Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses ISCIENCE Banerjee, A., El-Sayes, N., Budylowski, P., Jacob, R., Richard, D., Maan, H., Aguiar, J. A., Demian, W. L., Baid, K., D'Agostino, M. R., Ang, J., Murdza, T., Tremblay, B., Afkhami, S., Karimzadeh, M., Irving, A. T., Yip, L., Ostrowski, M., Hirota, J. A., Kozak, R., Capellini, T. D., Miller, M. S., Wang, B., Mubareka, S., McGeer, A. J., McArthur, A. G., Doxey, A. C., Mossman, K. 2021; 24 (5): 102477

  Abstract

  Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells.

  View details for DOI 10.1016/j.isci.2021.102477

  View details for Web of Science ID 000653990500086

  View details for PubMedID 33937724

  View details for PubMedCentralID PMC8074517