Jessica Kain

All Publications

• Mendelian randomization and pathway analysis demonstrate shared genetic associations between lupus and coronary artery disease. Cell reports. Medicine Kain, J., Owen, K. A., Marion, M. C., Langefeld, C. D., Grammer, A. C., Lipsky, P. E. 2022; 3 (11): 100805

  Abstract

  Coronary artery disease (CAD) is a leading cause of death in patients with systemic lupus erythematosus (SLE). Despite clinical evidence supporting an association between SLE and CAD, pleiotropy-adjusted genetic association studies are limited and focus on only a few common risk loci. Here, we identify a net positive causal estimate of SLE-associated non-HLA SNPs on CAD by traditional Mendelian randomization (MR) approaches. Pathway analysis using SNP-to-gene mapping followed by unsupervised clustering based on protein-protein interactions (PPIs) identifies biological networks composed of positive and negative causal sets of genes. In addition, we confirm the casual effects of specific SNP-to-gene modules on CAD using only SNP mapping to each PPI-defined functional gene set as instrumental variables. This PPI-based MR approach elucidates various molecular pathways with causal implications between SLE and CAD and identifies biological pathways likely causative of both pathologies, revealing known and novel therapeutic interventions for managing CAD in SLE.

  View details for DOI 10.1016/j.xcrm.2022.100805

  View details for PubMedID 36334592

  View details for PubMedCentralID PMC9729823

• Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα. Molecular metabolism Kain, J., Wei, X., Reddy, N. A., Price, A. J., Woods, C., Bochkis, I. M. 2021; 53: 101291

  Abstract

  Type II nuclear hormone receptors, including farnesoid X receptors (FXR), liver X receptors (LXR), and peroxisome proliferator-activated receptors (PPAR), which serve as drug targets for metabolic diseases, are permanently positioned in the nucleus and thought to be bound to DNA regardless of the ligand status. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent binding of type II nuclear receptors and performed genome-wide studies to test this hypothesis.ATAC-Seq was used to profile chromatin accessibility; ChIP-Seq was performed to assess transcription factors (Foxa2, FXR, LXRα, and PPARα) binding; and RNA-Seq analysis determined differentially expressed genes in wildtype and Foxa2 mutants treated with a ligand (GW4064 for FXR, GW3965, and T09 for LXRα).We reveal that chromatin accessibility, FXR binding, LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that Foxa2 interacts with either receptor in a ligand-dependent manner, suggesting that Foxa2 and the receptor, bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in Foxa2 mutants treated with FXR and LXR ligands, leading to the activation of PPARα targets.Our model requires pioneering activity for ligand activation that challenges the existing ligand-independent binding mechanism. We also demonstrate that Foxa2 is required to achieve activation of the proper receptor - one that binds the added ligand - by repressing the activity of a competing receptor.

  View details for DOI 10.1016/j.molmet.2021.101291

  View details for PubMedID 34246806

  View details for PubMedCentralID PMC8350412

• Considerations for reporting variants in novel candidate genes identified during clinical genomic testing. Genetics in medicine : official journal of the American College of Medical Genetics Chong, J. X., Berger, S. I., Baxter, S., Smith, E., Xiao, C., Calame, D. G., Hawley, M. H., Rivera-Munoz, E. A., DiTroia, S., Bamshad, M. J., Rehm, H. L. 2024: 101199

  Abstract

  Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

  View details for DOI 10.1016/j.gim.2024.101199

  View details for PubMedID 38944749

• Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases. Nature genetics Guo, M. G., Reynolds, D. L., Ang, C. E., Liu, Y., Zhao, Y., Donohue, L. K., Siprashvili, Z., Yang, X., Yoo, Y., Mondal, S., Hong, A., Kain, J., Meservey, L., Fabo, T., Elfaki, I., Kellman, L. N., Abell, N. S., Pershad, Y., Bayat, V., Etminani, P., Holodniy, M., Geschwind, D. H., Montgomery, S. B., Duncan, L. E., Urban, A. E., Altman, R. B., Wernig, M., Khavari, P. A. 2023

  Abstract

  Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

  View details for DOI 10.1038/s41588-023-01533-5

  View details for PubMedID 37857935

  View details for PubMedCentralID 4112379

• Beyond the exome: What's next in diagnostic testing for Mendelian conditions. American journal of human genetics Wojcik, M. H., Reuter, C. M., Marwaha, S., Mahmoud, M., Duyzend, M. H., Barseghyan, H., Yuan, B., Boone, P. M., Groopman, E. E., Délot, E. C., Jain, D., Sanchis-Juan, A., Starita, L. M., Talkowski, M., Montgomery, S. B., Bamshad, M. J., Chong, J. X., Wheeler, M. T., Berger, S. I., O'Donnell-Luria, A., Sedlazeck, F. J., Miller, D. E. 2023; 110 (8): 1229-1248

  Abstract

  Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

  View details for DOI 10.1016/j.ajhg.2023.06.009

  View details for PubMedID 37541186

• Systemic lupus erythematosus and cardiovascular disease: A Mendelian randomization study FRONTIERS IN IMMUNOLOGY Kerns, S., Owen, K. A., Kain, J., Lipsky, P. E. 2022; 13: 1075400

  View details for DOI 10.3389/fimmu.2022.1075400

  View details for Web of Science ID 000902138400001

  View details for PubMedID 36569872

  View details for PubMedCentralID PMC9773385

• Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver. Aging cell Price, A. J., Manjegowda, M. C., Kain, J., Anandh, S., Bochkis, I. M. 2020; 19 (2): e13092

  Abstract

  Post-translational modifications of histone tails play a crucial role in gene regulation. Here, we performed chromatin profiling by quantitative targeted mass spectrometry to assess all possible modifications of the core histones. We identified a bivalent combination, a dually marked H3K9me3/H3K14ac modification in the liver, that is significantly decreased in old hepatocytes. Subsequent sequential ChIP-Seq identified dually marked single nucleosome regions, with reduced number of sites and decreased signal in old livers, confirming mass spectrometry results. We detected H3K9me3 and H3K14ac bulk ChIP-Seq signal in reChIP nucleosome regions, suggesting a correlation between H3K9me3/H3K14ac bulk bivalent genomic regions and dually marked single nucleosomes. Histone H3K9 deacetylase Hdac3, as well as H3K9 methyltransferase Setdb1, found in complex Kap1, occupied both bulk and single nucleosome bivalent regions in both young and old livers, correlating to presence of H3K9me3. Expression of genes associated with bivalent regions in young liver, including those regulating cholesterol secretion and triglyceride synthesis, is upregulated in old liver once the bivalency is lost. Hence, H3K9me3/H3K14ac dually marked regions define a poised inactive state that is resolved with loss of one or both of the chromatin marks, which subsequently leads to change in gene expression.

  View details for DOI 10.1111/acel.13092

  View details for PubMedID 31858687

  View details for PubMedCentralID PMC6996956