About

Isaac Hilton is an Associate Professor of Bioengineering at Rice University and a CPRIT Scholar in Cancer Research. He is a pioneer in developing cutting-edge biotechnologies, including CRISPR/Cas systems, gene delivery platforms, and synthetic gene circuitry, to decode human gene regulatory logic and engineer cellular behaviors. Hilton’s team builds robust, accessible platforms for precision synthetic biology and next-generation cell-based therapeutics, investigating how the human genome is regulated in health and disease. His research involves engineering human cells for discovery and medicine by making gene regulation and cellular functions programmable, connecting fundamental insights in human cell biology to translational advances. Hilton earned his PhD at the University of North Carolina at Chapel Hill, where he studied human epigenetics and tumor virology, developing high-throughput genomics approaches to understand pathological chromatin architecture and gene expression in virus-infected cancer cells. As a postdoctoral fellow at Duke University, he built some of the first programmable CRISPR/Cas9-based epi-editing platforms, including a CRISPR-based acetyltransferase recognized as one of The Scientist’s Top Ten Innovations of 2015. Since joining Rice University in 2018 through a CPRIT Cancer Scholar Award, Hilton has led his laboratory in advancing genome and epigenome editing technologies, synthetic genetic control in human cells, therapeutic cell engineering, and training future leaders in biomedical research and bioengineering. His team also pursues translation and commercialization, with lab members serving as inventors on patents related to genome/epigenome editing and cell engineering.

Research topics

• Biology
• Computational biology
• Genetics
• Cell biology
• Computer Science
• Nanotechnology
• Medicine
• Chemistry
• Chemical engineering
• Materials science
• Risk analysis (engineering)
• Mathematics
• Data science
• Surgery
• Immunology
• Biomedical engineering
• Business
• Biochemistry

Selected publications

• CRISPR-Cas-based activation of PPARGC1A boosts endogenous mitochondria and enhances cardiac function after myocardial infarction

  Molecular Therapy · 2026-03-01

  articleOpen accessSenior author

  Insufficient energy supply due to impaired mitochondria has emerged as a key pathological factor in the development of heart failure (HF) after myocardial infarction (MI). Unfortunately, no current therapeutic strategies directly augment myocardial energy production. While mitochondrial biogenesis is orchestrated by the activity of multiple genes, activation of PPARGC1A, a key regulator, can increase cellular mitochondria; however, supraphysiological levels of PPARGC1A result in adverse tissue remodeling and heart dysfunction. CRISPR activation (CRISPRa) technologies present a unique opportunity to address these shortcomings, as they enable tunable control over endogenous target gene expression. Here, we demonstrate that transcriptional activation of PPARGC1A using CRISPRa increases cellular mitochondria in human cell types. This effect is mediated through the activation of transcriptional programs driving mitochondrial biogenesis, mitochondrial function, and cellular bioenergetics. These activated transcriptional programs synergize to increase ATP production and reserve capacity in human cardiomyocytes. CRISPRa targeting of PPARGC1A in vivo increases cardiac mitochondria to recover heart ejection fraction in an acute MI model. Furthermore, CRISPRa acts on the adult human heart to increase PPARGC1A protein and cellular mitochondria, elevating mitochondrial function in both normal and HF-diagnosed hearts. These results provide the first proof of concept that endogenous gene activation via CRISPRa can improve heart function after MI.

  PublisherDOI

• Clinical translation of epigenome editing technologies

  Current Opinion in Biomedical Engineering · 2026-04-17 · 1 citations

  articleSenior author
  PublisherDOI

• Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in cardiomyocytes

  2026-02-04

  article

  Background and purpose: Cardiomyocyte (CM) cell cycle exit following neonatal stages positively correlates with epigenetic reprogramming that driving postnatal maturation as defined by increased rigidity of the sarcomere and metabolic reprogramming. However, till date, the epigenetic driver(s) for such process has not been identified. In this study, through a small molecule screening, we defined the histone lysine demethylase, Kdm5b , as a major epigenetic driver that controls the CM cell cycle gene expression in neonatal stage and can be reintroduced in adult CMs to induce cell cycle. Experimental approach and key results: By screening a histone modification small molecule library, we identified AS-8531, a Kdm5b inhibitor , as a potent inhibitor of CM cell cycle. Furthermore, Kdm5b knockdown (KD) using shRNA or CM specific knockout mice in naturally proliferating CMs isolated from postnatal day 1 neonatal mouse hearts (NMCM P1) reduced CM proliferation. While Kdm5b overexpression in adult mouse hearts and human heart slices enhances CM proliferation and augment the induced CM proliferation using other cell cycle factors, indicating that Kdm5b is an epigenetic driver that drive CM genetic program that govern CM cell cycle. Mechanistically, RNAseq and CUT&RUN analyses of Kdm5b KD in NMCM P1 revealed that Kdm5b modulates the expression and the enrichment of H3K4me3 methylation around the regulatory regions of the genes involved in cell cycle. Conclusion: Kdm5b functions as an epigenetic driver that regulates the transcription of key factors controlling CM cell cycle. Overexpression of Kdm5b represents a potential strategy to induce regenerative capacity in adult CMs.

  PublisherDOI

• Author response: Predicting the effect of CRISPR-Cas9-based epigenome editing

  2026-01-12

  peer-reviewOpen access

  Machine learning models reveal that histone marks are predictive of gene expression across human cell types and highlight important nuances between natural control and the effects of CRISPR-Cas9-based epigenome editing.

  PublisherDOI

• Predicting the effect of CRISPR-Cas9-based epigenome editing

  eLife · 2026-01-12

  articleOpen access

  Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ∼0.70−0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together, these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.

  PublisherDOI

• Robust fluorescent labeling and tracking of endogenous non-repetitive genomic loci

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-27 · 2 citations

  preprintOpen access

  Abstract The spatial organization and dynamics of a genome are central to gene regulation. While a comprehensive understanding of chromatin organization in the human nucleus has been achieved using fixed-cell methods, measuring the dynamics of specific genomic regions over extended periods in individual living cells remains challenging. Here, we present a robust and fully genetically encoded system for fluorescent labeling and long-term tracking of any accessible non-repetitive genomic locus in live human cells using fluorogenic and replenishable nanobody array fusions of the Staphylococcus aureus dCas9, and compact polycistronic single guide (sg)RNAs. First, we characterize the selectivity and photostability of our probes, enabling genome-wide visualization of chromatin dynamics at locally repetitive elements. Next, through multiplexed expression of 8–10 sgRNAs from polycistronic cassettes, we demonstrate efficient and sustained labeling of non-repetitive loci, enabling high-fidelity tracking of gene-proximal regions at exceptional spatial and temporal resolution. Finally, by correlating chromatin mobility with transcriptional activity at multiple genes, we find that local chromatin dynamics at 20 Hz are gene-specific and not necessarily dependent on transcription. Our approach is versatile, minimally invasive, and scalable, enabling multiplexed imaging of regulatory element dynamics involved in gene control, with broad applicability across diverse biological systems and disease contexts.

  PublisherOA PDFDOI

• Author response: Predicting the effect of CRISPR-Cas9-based epigenome editing

  2025-05-27

  peer-reviewOpen access

  Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ∼ 0.70 − 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.

  PublisherDOI

• Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization

  Nucleic Acids Research · 2025-01-22 · 5 citations

  articleOpen accessSenior author

  Protein intrinsically disordered regions (IDRs) are critical gene-regulatory components and aberrant fusions between IDRs and DNA-binding/chromatin-associating domains cause diverse human cancers. Despite this importance, how IDRs influence gene expression, and how aberrant IDR fusion proteins provoke oncogenesis, remains incompletely understood. Here we develop a series of synthetic dCas9-IDR fusions to establish that locus-specific recruitment of IDRs can be sufficient to stimulate endogenous gene expression. Using dCas9 fused to the paradigmatic leukemogenic NUP98 IDR, we also demonstrate that IDRs can activate transcription via localized biomolecular condensation and in a manner that is dependent upon overall IDR concentration, local binding density, and amino acid composition. To better clarify the oncogenic role of IDRs, we construct clinically observed NUP98 IDR fusions and show that, while generally non-overlapping, oncogenic NUP98-IDR fusions convergently drive a core leukemogenic gene expression program in donor-derived human hematopoietic stem cells. Interestingly, we find that this leukemic program arises through differing mechanistic routes based upon IDR fusion partner; either distributed intragenic binding and intrachromosomal looping, or dense binding at promoters. Altogether, our studies clarify the gene-regulatory roles of IDRs and, for the NUP98 IDR, connect this capacity to pathological cellular programs, creating potential opportunities for generalized and mechanistically tailored therapies.

  PublisherDOI

• Integrating synthetic biology to understand and engineer the heart, lung, blood, and sleep systems

  Cell Systems · 2025-12-01

  articleOpen access
  PublisherOA PDFDOI

• Predicting the effect of CRISPR-Cas9-based epigenome editing

  eLife · 2025-05-27

  preprintOpen access

  Abstract Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ∼ 0.70 − 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.

  PublisherDOI

Recent grants

• Engineering Therapeutic Human Immune Cells with Modular Self-contained Genetic Circuits

  NIH · $604k · 2021–2024

• Site-specific control of human gene regulation for therapeutically applicable mechanistic insights

  NIH · $1.9M · 2021–2026

Frequent coauthors

• Alan Cabrera

  Rice University

  82 shared

• Jeffrey P. Spence

  Stanford University

  74 shared

• Sanjit Singh Batra

  University of California, Berkeley

  74 shared

• Yun S. Song

  University of California, Berkeley

  62 shared

• Dirk P. Dittmer

  University of North Carolina at Chapel Hill

  19 shared

• Blossom Damania

  16 shared

• Kristen M. Tamburro

  15 shared

• Veenadhari Chavakula

  15 shared

Labs

• Hilton LabPI

Education

• Doctor of Philosophy, Genetics and Molecular Biology

  University of North Carolina at Chapel Hill

  2013

• Bachelor of Science, Biological Sciences

  University of Missouri Columbia

  2004

Awards & honors

• Duke University Center for Biomolecular and Tissue Engineeri…
• CRISPR-based acetyltransferase recognized as one of The Scie…
• CPRIT Scholar in Cancer Research (2018)