About

David J. Waxman is a Professor of Biology, Medicine, and Biomedical Engineering at Boston University, with a PhD from Harvard University. His research program encompasses three major projects focused on understanding gene regulation and epigenetic mechanisms in mammalian tissues. His work investigates how hormone regulatory circuits, epigenetic modifiers, and long non-coding RNA genes interact to regulate complex gene expression patterns, particularly in the liver, and how environmental chemicals influence these processes, leading to developmental and adult diseases such as fatty liver disease, NASH, and hepatocellular carcinoma. Additionally, Waxman explores cancer therapy, specifically how host-tumor interactions and immune responses can be modulated through novel treatment schedules like metronomic chemotherapy to activate innate immune signaling pathways and improve therapeutic outcomes. His research employs advanced sequencing technologies, bioinformatics analysis, and in vivo models to elucidate regulatory networks, epigenetic states, and mechanisms underlying sex differences in liver gene expression, as well as the impact of environmental exposures on developmental and disease processes.

Research topics

• Biology
• Medicine
• Internal medicine
• Genetics
• Cancer research
• Chemistry
• Artificial Intelligence
• Endocrinology
• Computer Science
• Biochemistry
• Computational biology
• Cell biology
• Pathology
• Mathematics
• Radiology

Selected publications

• <b>Supplementary Information to "Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism"</b>

  Figshare · 2026-04-09

  otherOpen accessSenior author

  Growth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5B^Y665F (gain-of-function) and STAT5B^Y665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5B^Y665F mice developed hypercholesterolemia and enhanced insulin sensitivity, whereas STAT5B^Y665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5B^Y665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5B^Y665H failed to induce these pathways. Notably, STAT5B^Y665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5B^Y665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5B^Y665H. Beyond the liver, STAT5B^Y665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5B^Y665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

  PublisherDOI

• Suppl Figs and Suppl Tables_Chang and Waxman_Endocrinology_2026

  Figshare · 2026-03-25

  datasetOpen accessSenior author

  Supplemental Figures, S1 to S15, and Supplemental Tables, S1 to S13, for a study by Chang and Waxman (Endocrinology, 2026), entitled: <b>HDI-STARR-seq Identifies Functional GH-regulated Sex-Biased Hepatocyte Enhancers Linked to Liver Metabolism and Disease</b>.<b>Abstract</b>: Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional <i>cis</i>-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with <i>in vivo</i> functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23,912 reporters spanning 1,839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling enhancer activity assessment across different biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring regulation of their accessibility in hepatocyte chromatin, validating them as functional, physiologically regulated enhancers. The regulated enhancer sequences were enriched for activating histone marks (H3K27ac, H3K4me1), and for binding sites for the STAT5-dependent, sex-specific repressors BCL6 and CUX2; whereas, STAT5 binding was enriched at both regulated and non-regulated enhancers. Motifs for HNF4A and for several novel factors identified <i>de novo</i> were specifically enriched at the regulated enhancers. Sex-biased and GH-regulated enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated <i>in vivo</i> approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and MASLD risk.

  PublisherDOI

• Suppl Figs and Suppl Tables_Chang and Waxman_Endocrinology_2026

  Figshare · 2026-03-25

  datasetOpen accessSenior author

  Supplemental Figures, S1 to S15, and Supplemental Tables, S1 to S13, for a study by Chang and Waxman (Endocrinology, 2026), entitled: <b>HDI-STARR-seq Identifies Functional GH-regulated Sex-Biased Hepatocyte Enhancers Linked to Liver Metabolism and Disease</b>.<b>Abstract</b>: Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional <i>cis</i>-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with <i>in vivo</i> functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23,912 reporters spanning 1,839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling enhancer activity assessment across different biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring regulation of their accessibility in hepatocyte chromatin, validating them as functional, physiologically regulated enhancers. The regulated enhancer sequences were enriched for activating histone marks (H3K27ac, H3K4me1), and for binding sites for the STAT5-dependent, sex-specific repressors BCL6 and CUX2; whereas, STAT5 binding was enriched at both regulated and non-regulated enhancers. Motifs for HNF4A and for several novel factors identified <i>de novo</i> were specifically enriched at the regulated enhancers. Sex-biased and GH-regulated enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated <i>in vivo</i> approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and MASLD risk.

  PublisherDOI

• HDI-STARR-seq identifies functional GH-regulated sex-biased hepatocyte enhancers linked to liver metabolism and disease

  Endocrinology · 2026-03-19 · 1 citations

  articleSenior author

  Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with in vivo functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23 912 reporters spanning 1839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling enhancer activity assessment across different biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring regulation of their accessibility in hepatocyte chromatin, validating them as functional, physiologically regulated enhancers. The regulated enhancer sequences were enriched for activating histone marks (H3K27ac, H3K4me1), and for binding sites for the STAT5-dependent, sex-specific repressors BCL6 and CUX2; whereas, STAT5 binding was enriched at both regulated and non-regulated enhancers. Motifs for HNF4A and for several novel factors identified de novo were specifically enriched at the regulated enhancers. Sex-biased and GH-regulated enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated in vivo approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and MASLD risk.

  PublisherDOI

• <b>Supplementary Information to "Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism"</b>

  Figshare · 2026-04-09

  otherOpen accessSenior author

  Growth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5B^Y665F (gain-of-function) and STAT5B^Y665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5B^Y665F mice developed hypercholesterolemia and enhanced insulin sensitivity, whereas STAT5B^Y665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5B^Y665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5B^Y665H failed to induce these pathways. Notably, STAT5B^Y665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5B^Y665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5B^Y665H. Beyond the liver, STAT5B^Y665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5B^Y665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

  PublisherDOI

• Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-01

  preprintOpen accessSenior authorCorresponding

  Growth hormone (GH) signaling through signal transducer and activator of transcription 5 (STAT5B) is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5BY665F mice developed hypercholesterolemia and enhanced insulin sensitivity, whereas STAT5BY665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5BY665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. Notably, STAT5BY665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5BY665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5BY665H. Beyond the liver, STAT5BY665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5BY665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

  PublisherDOI

• Single Nucleus MultiOmics Links Novel Transcription Factor Motifs to Murine Hepatic Sex Differences in Chromatin Accessibility and Metabolic Dysfunction-Associated Steatotic Liver Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-31 · 1 citations

  preprintOpen accessSenior authorCorresponding

  The liver exhibits striking sexual dimorphism in gene expression that impacts drug and lipid metabolism and disease susceptibility, with males showing substantially higher predisposition to metabolic dysfunction-associated steatotic liver disease (MASLD) and its complications including hepatocellular carcinoma. These sex differences are primarily controlled by sexually dimorphic pituitary growth hormone (GH) secretion patterns; however, the underlying transcriptional and epigenetic regulatory networks remain only partially understood. Here, we generated paired single-nucleus chromatin accessibility (snATAC-seq) and gene expression (snRNA-seq) profiles from 46,188 liver nuclei isolated from male, female and continuous GH-infused male mice to comprehensively map the epigenetic basis of hepatic sexual dimorphism. We identified 127,957 accessible chromatin regions genome-wide, including thousands of novel regions enriched specifically in non-parenchymal cells. Sex-biased differentially accessible chromatin regions (DARs) were almost exclusively hepatocyte-localized, and continuous GH infusion feminized their accessibility, demonstrating that plasma GH patterns alone are sufficient to reprogram sex-biased hepatocyte chromatin landscapes. Correlation-based peak-to-gene linkage analysis mapped these DARs to sex-biased gene targets and revealed that regulatory interactions are constrained by topologically associated domain boundaries. Motif enrichment analysis identified both established regulators (STAT5, CUX2, BCL6) and novel transcription factors (TFs) at sex-biased DARs. ATAC-seq footprinting revealed novel TF motifs predicted to be occupied at DARs linked to sex-biased genes implicated in MASLD, providing mechanistic insights into the male bias in fatty liver disease. Further, motif co-occurrence analysis revealed TF clusters likely cooperating to regulate sex-dependent gene expression programs. We also identified stringently cell type-specific regulatory regions with cell type-specific TF motifs that define the regulatory architecture underlying hepatocyte and non-parenchymal cell identities. This comprehensive multiOmic atlas elucidates TF networks controlling sex-dependent liver gene expression and serves as a foundational resource for understanding molecular mechanisms underlying sex disparities in MASLD and other liver diseases.

  PublisherDOI

• Recent Developments In Cannabis Law 2024

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• HDI-STARR-seq Identifies Functional GH-regulated Sex-Biased Hepatocyte Enhancers Linked to Liver Metabolism and Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-04

  preprintOpen accessSenior authorCorresponding

  Abstract Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Despite extensive study of GH-regulated sex differences in gene transcription, the functional cis -regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with in vivo functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23,912 reporters spanning 1,839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling functional assessment of enhancer activity in vivo across distinct biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring the regulation of their chromatin accessibility in hepatocytes, validating these sites as functional, physiologically regulated enhancers. The regulated enhancers were enriched for activating histone marks (H3K4me1, H3K27ac), for binding sites for the GH-activated transcriptional regulator STAT5, and for the STAT5-dependent, sex-specific repressors BCL6 and CUX2. Further, de novo motif analysis identified binding sites for HNF4A and for several novel factors specifically enriched at the regulated enhancers. Sex-biased and GH-regulated functional enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated in vivo approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and sex-specific MASLD risk.

  PublisherDOI

• Unexpected unbalanced upregulation of genes in gene replacement therapy with a constitutively active promoter and growth hormone receptor (GHR) in mice with nonfunctional GHR (laron mice)

  Endocrine Abstracts · 2025-05-09

  articleSenior author
  PublisherDOI

Recent grants

• Xenobiotic-responsive hepatic long non-coding RNAs

  NIH · $4.6M · 2014–2026

• Regulation of sex differences in liver metabolism

  NIH · $206k · 1999–2019

• NIH Grant RC1ES018332

  NIH · $892k · 2012

• NIH Grant R01AM033765

  NIH · $122k · 1987

• Growth Hormone Regulation of Sex Differences in Liver Metabolism

  NIH · $2.5M · 2019–2025

Frequent coauthors

• D P Lapenson

  112 shared

• Frank J. Gonzalez

  Colciencias

  98 shared

• Gert Kreibich

  New York University

  62 shared

• Ai‐Ming Yu

  50 shared

• Chong-Sheng Chen

  50 shared

• Kristopher W. Krausz

  50 shared

• Connie Cheung

  Westmead Institute for Medical Research

  49 shared

• Robert J. Edwards

  Harvard University

  49 shared