About

Klaus H. Kaestner, Ph.D., is the Thomas and Evelyn Suor Butterworth Professor in Genetics at the University of Pennsylvania Perelman School of Medicine and serves as Associate Director of the Diabetes Research Center. His research employs modern genetic, genomic, and epigenomic approaches—including ChIP-Seq, RNA-Seq, gene targeting, tissue-specific and inducible gene ablation, and CyTOF—to understand the molecular mechanisms of organogenesis and physiology of the liver, pancreas, and gastrointestinal tract. His work targets disease areas such as diabetes and cancer, with a focus on the epigenomic rejuvenation of human pancreatic beta-cells, mechanisms of age-related decline in beta-cell function, and the regulation of gastrointestinal epithelium differentiation and proliferation. Dr. Kaestner's laboratory aims to develop innovative strategies for increasing beta-cell mass, understanding liver response to toxic injury, and improving cell replacement therapies for chronic liver disease, leveraging insights from human disease and aging to facilitate translational applications.

Research topics

• Biology
• Genetics
• Bioinformatics
• Medicine
• Internal medicine
• Computational biology
• Cell biology
• Endocrinology
• Political Science
• Pharmacology
• Pathology
• Chemistry
• Neuroscience
• Cancer research
• Physiology
• Audiology
• Surgery

Selected publications

• TNFSF13 insufficiency disrupts human colonic epithelial cell growth and associated B cell dynamics

  Journal of Clinical Investigation · 2026-03-31

  articleOpen access

  Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.

  PublisherDOI

• Addendum: Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1

  Nature Communications · 2026-05-01

  articleOpen access

  In this article, the authors reported an engineered mouse model, termed 'Telomouse', with a missense mutation in Rtel1 (methionine 492 to a lysine; Rtel1 M492K ).The design of the Telomouse strain was based on the genetic association of Rtel1 with telomere length, as identified by crossing Mus spretus with short telomeres to M. musculus with long telomeres 1 , and on the presence of the Rtel1 M492K variation in the M. spretus Rtel1 transcripts sequences available at the time 2 .The authors hypothesized that this variation was responsible for the shorter telomeres of M. spretus, as compared with M. musculus, and predicted that a M. musculus strain harboring this mutation would also shorten its telomeres.While Telomice homozygous for the Rtel1 M492K mutation indeed shortened their telomeres as predicted, the more recently available M. spretus genome 3 revealed no such variation in Rtel1.Furthermore, the authors obtained DNA samples from two available M. spretus strains 4,5 , PCR-sequenced this part of Rtel1, and found that both strains have a methionine at position 492.M. spretus appears highly heterogenous 6 and the authors cannot exclude the possibility that the original strain used for the cDNA sequencing indeed had a lysine at position 492.However, since two currently used M. spretus strains have short telomeres but not the Rtel1 M492K variation, such a variation cannot explain the short telomeres in this species.Importantly, introducing Rtel1 M492K mutation into M. musculus resulted in short, stable, human-length telomeres in an invaluable model for studying the roles of telomeres in cancer and aging.

  PublisherDOI

• Epigenetic adaptation of beta cells across lifespan and disease

  Nature Metabolism · 2026-04-24 · 3 citations

  articleOpen access

  Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycaemia despite rising insulin resistance owing to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here we show the mapping of genome-wide DNA methylation (DNAm) patterns and the epigenomic basis of beta cell adaptations by leveraging cell-type-specific methylome data from the Human Pancreas Analysis Program. In healthy donors, we identify progressive age-related demethylation enriched in cis-regulatory elements at beta cell identity and function genes. By contrast, alpha cells show the opposite trajectory, with subtle, age-related hypermethylation. In T2D beta cells, but not alpha cells, we observed further demethylation compared to healthy controls, underscoring a unique capacity of beta cells to respond to changes in metabolic demand. Together, our findings suggest that DNAm remodelling in healthy beta cells reflects a long-term adaptation to metabolic demand, which, in T2D, is accelerated as part of a compensatory response that ultimately fails under sustained insulin resistance.

  PublisherOA PDFDOI

• Spatial atlas of diabetic kidney disease reveals a B cell-rich subgroup

  Nature · 2026-04-29

  article
  PublisherDOI

• Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1

  Nucleic Acids Research · 2025-05-29 · 3 citations

  articleOpen access

  RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. The ultra-long telomeres of the house mouse hinder its utility as a model for telomere-related diseases. We have previously generated a mouse model with human-length telomeres, termed "Telomouse," by substituting methionine 492 of mouse Rtel1 to a lysine (Rtel1M492K). In humans, a methionine to isoleucine mutation at this position causes the fatal telomere biology disorder Hoyeraal-Hreidarsson syndrome (HHS). Here, we introduced the Rtel1M492I point mutation into the mouse genome, generating another mouse model, which we termed "HHS mouse." The HHS mouse telomeres are not as short as those of the Telomouse but nevertheless display higher levels of telomeric DNA damage, fragility, and recombination, associated with anaphase bridges and micronuclei. The HHS mouse also exhibits aberrant hematopoiesis and pre-fibrotic alterations in the lung. These observations indicate that the two mutations at the same codon separate critical functions of RTEL1: Rtel1M492K mainly reduces the telomere length setpoint, while Rtel1M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology disorders and genomic instability.

  PublisherDOI

• Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-30

  preprintOpen accessSenior authorCorresponding

  Abstract Extremely short telomeres cause bone marrow failure in telomere biology disorder (TBDs) patients. Here, we employed the recently developed ‘Telomouse’ with human-length telomeres resulting from a single amino acid substitution in the helicase Rtel1 ( Rtel1 M492K/M492K ) to determine the effects of the short telomeres on the bone marrow and hematopoiesis. Under homeostatic conditions, Telomice have notably short telomeres but normal hematopoiesis. However, when forced to repopulate following repeated treatment with 5-fluoro-uracil or upon bone marrow transplantation into lethally irradiated mice, bone marrow progenitor cells are significantly depleted in Telomice compared to wild-type controls. This effect is associated with increased frequency of telomere repeat arrays too short to be detected by fluorescence in situ hybridization in the bone marrow of Telomice.

  PublisherOA PDFDOI

• 3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

  Genome biology · 2025-12-08 · 1 citations

  articleOpen access

  Abstract Background Insight into the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but this alone does not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. Results Here, we generate 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrate this data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. The majority of variants implicated by these cis-regulatory architectures are trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, leading to enrichment of similar biological networks. While this suggests a high level of genetic diversity and complexity that converges at the level of target gene and cell type, some trait-specific pathways representing potential areas for disease-specific intervention were identified. We pharmacologically validate squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach and supported by prior eQTL data in multiple sclerosis and systemic lupus erythematosus, as a novel immunomodulatory drug target controlling T cell inflammatory cytokine production and aiding B cell antibody production in a human lymphoid organoid model. Conclusions These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types. Graphical Abstract

  PublisherDOI

• Accelerating Medicines Partnerships<sup>®</sup> in Type 2 Diabetes and Common Metabolic Diseases: collaborating to maximize the value of genetic and genomic data

  2025-04-24

  preprintOpen access

  <p dir="ltr">In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnerships<sup>®</sup> in Type 2 Diabetes (AMP<sup>®</sup> T2D) and Common Metabolic Diseases (AMP<sup>®</sup> CMD). These public-private partnerships between the National Institutes of Health (NIH), multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the NIH (FNIH), were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK’s 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership been pivotal to the partnerships’ success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK’s mission to conduct research and share results with the goal of improving health and quality of life.</p>

  PublisherOA PDFDOI

• Accelerating Medicines Partnership in Type 2 Diabetes and Common Metabolic Diseases: Collaborating to Maximize the Value of Genetic and Genomic Data

  Diabetes · 2025-04-24 · 2 citations

  reviewOpen access

  In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of Health, multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the National Institutes of Health, were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK's 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership have been pivotal to the partnerships' success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK's mission to conduct research and share results with the goal of improving health and quality of life. ARTICLE HIGHLIGHTS: The Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD) were created to accelerate the translation of genetic and genomic data into knowledge about the biology of disease. Their goal was to gain a better understanding of the mechanisms underlying types 1 and 2 diabetes and prediabetes, obesity, cardiovascular disease, kidney disease, and nonalcoholic steatohepatitis. This work identified multiple genes and pathways underlying these diseases. The findings of AMP T2D and AMP CMD have implications for drug development and improved risk prediction, diagnosis, and treatment for common metabolic diseases.

  PublisherOA PDFDOI

• Accelerating Medicines Partnership in Type 2 Diabetes and Common Metabolic Diseases: Collaborating to Maximize the Value of Genetic and Genomic Data.

  UNC Libraries · 2025-11-07

  articleOpen access

  In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of Health, multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the National Institutes of Health, were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK's 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership have been pivotal to the partnerships' success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK's mission to conduct research and share results with the goal of improving health and quality of life. ARTICLE HIGHLIGHTS: The Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD) were created to accelerate the translation of genetic and genomic data into knowledge about the biology of disease. Their goal was to gain a better understanding of the mechanisms underlying types 1 and 2 diabetes and prediabetes, obesity, cardiovascular disease, kidney disease, and nonalcoholic steatohepatitis. This work identified multiple genes and pathways underlying these diseases. The findings of AMP T2D and AMP CMD have implications for drug development and improved risk prediction, diagnosis, and treatment for common metabolic diseases.

  PublisherDOI

Recent grants

• NIH Grant UC4DK104119

  NIH · $3.6M · 2019

• NIH Grant R01DK053839

  NIH · $4.9M · 2012

• NIH Grant U01DK089569

  NIH · $5.3M · 2016

• NIH Grant U01DK089529

  NIH · $1.8M · 2014

• University of Pennsylvania Diabetes Research Center

  NIH · $17.0M · 1997–2027

Frequent coauthors

• Jonathan Schug

  96 shared

• Ali Naji

  Hospital of the University of Pennsylvania

  54 shared

• Siew‐Lan Ang

  The Francis Crick Institute

  47 shared

• Franz M. Matschinsky

  University of Pennsylvania

  46 shared

• Doris A. Stoffers

  University of Pennsylvania

  44 shared

• Catherine Lee May

  University of Pennsylvania

  38 shared

• Daniel Traum

  37 shared

• Yue J. Wang

  35 shared

Labs

• Kaestner LaboratoryPI

Education

• Ph.D., Biochemistry, Cellular and Molecular Biology

  Johns Hopkins School of Medicine

  1990

Awards & honors

• Thomas and Evelyn Suor Butterworth Professor in Genetics