About

Andrew William Grimson is the Charles A. Alexander Professor of Biological Sciences in the Department of Molecular Biology & Genetics. He is a member of the Graduate Field of Biochemistry, Molecular and Cell Biology and the Graduate Field of Genetics, Genomics and Development. His laboratory focuses on post-transcriptional gene regulation, particularly the identity and function of animal microRNAs and other small RNAs. His research investigates the function of small RNA regulatory molecules, chiefly microRNAs, and the identification and characterization of novel cis-regulatory elements within mRNAs. His work combines high-throughput experimental and computational genomics with traditional experimental approaches. Ongoing projects include fundamental studies in post-transcriptional regulation, such as mechanistic characterization of novel regulatory pathways, and investigations into biological roles for post-transcriptional regulation, including the roles of small RNAs in the mammalian immune system.

Research topics

• Biology
• Genetics
• Cell biology
• Immunology
• Cancer research
• Medicine
• Evolutionary biology
• Computational biology

Selected publications

• Single cell analysis of neonatal naïve CD8α ⁺ T cells reveals novel subsets bridging the innate-adaptive spectrum

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-09

  articleOpen access

  Abstract There is growing evidence that neonates harbor innate-like CD8a + T cell subsets that contribute to both protection and hyper-inflammatory states. It remains unclear, however, where these innate-like features are found among the many conventional and unconventional T cell populations that can upregulate the CD8 receptor. Further delineation of these unique populations and functions, with a focus on CD8ab co-expression, will enable studies that seek to understand the unique immune features in conventional T cell populations that are present during fetal and early postnatal life. We used cord blood from infants across the full viable gestational age range to examine phenotypic and transcriptional heterogeneity, with a particular focus on the naïve T cell pool. We report a set of fetally-derived and innate-like naïve CD8αβ + T cells (‘FITs’) that are marked by their KLRG1 + CD161 + phenotype, unique transcriptomic features and which are sparsely detected in adult peripheral blood. Additionally, using T cell receptor repertoire profiling, we can distinguish FITs from well-described and semi-invariant unconventional T cell populations such as mucosa-associated invariant T cells. Our delineation of FITs’ unique features will enable future investigation into their ontogeny and tissue distribution, and ultimately their role in immune-related outcomes in preterm infants.

  PublisherOA PDFDOI

• Single-cell gene expression and TCR profiling reveal age-related differences in recent thymic emigrants

  iScience · 2026-04-02

  articleOpen access

  RTEs and found that they exhibit distinct phenotypes and functions. Paired single-cell transcriptomics and T cell receptor (TCR) sequencing showed that neonatal RTEs exhibit a more effector-like gene expression profile than adult RTEs, and the most pronounced effector-gene bias was found in neonatal RTEs that utilize germline-encoded TCRs. Collectively, these data reveal how the RTE pool changes during development and how TCR usage contributes to phenotypic heterogeneity in the neonatal and adult RTE pools.

  PublisherDOI

• Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

  Proceedings of the National Academy of Sciences · 2025-08-11 · 4 citations

  articleOpen access

  People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes. We profiled cfRNA in plasma by RNA sequencing for 93 ME/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%. Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell-derived cfRNA in ME/CFS. Biological network analysis further implicated immune dysfunction in ME/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.

  PublisherOA PDFDOI

• Argonaute proteins regulate the timing of the spermatogenic transcriptional program

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-01 · 1 citations

  preprintOpen access

  ABSTRACT Argonaute proteins are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we show that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatocytes where they are required for transcriptional silencing of XY-linked genes, known as Meiotic Sex Chromosome Inactivation (MSCI). Using an Ago413 -/- mouse, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I while maintaining silencing of spermiogenesis genes. Premature overexpression of spermiogenesis genes during prophase I in Ago413 -/- mice results in subfertility, altered sperm morphology and reduced fertilization capability. We also identify BRG1, a BAF complex subunit, as an AGO3 interactor. Loss of AGO3 and AGO4 results in increased BRG1 in spermatocytes, suggesting that AGO3 aids in removing BRG1 from the XY chromatin to achieve MSCI and demonstrating a meiotic role for AGO3 in transcriptional control through the chromatin remodeling machinery.

  PublisherOA PDFDOI

• An efficient framework to decipher microRNA regulatory programs applied to T cells

  Genes and Immunity · 2025-08-18

  articleOpen accessSenior author

  Naïve CD8 + T cells are heterogenous, with subsets exhibiting divergent kinetics and functions post-activation. MicroRNAs, important mediators of post-transcriptional regulation, contribute to specification of different naïve T cell subsets. However, the microRNA regulatory circuits mediating functional specialization of naïve subsets are poorly understood. Here, we profiled microRNA expression in diverse subsets of naïve CD8 + T cells, revealing significant differences in their microRNA expression landscapes. We developed a novel framework, miR-Inf, to decipher microRNA regulatory programs. miR-Inf features two innovative attributes: (i) an efficient approach based on intron-exon ratios to estimate gene decay rates from a compendium of RNA-seq profiles, in order to better capture microRNA regulatory effects, and (ii) identification of cell-type-specific microRNA targets by integrating decay rate data and microRNA expression data. We applied this framework to identify consequential miRNAs in naïve CD8 + T cell subsets and predicted their subset-specific targets. Our analyses revealed that miR-29, a microRNA known to be important in CD8 + T cells, likely functions by modulating transcripts encoding epigenetic factors, thereby pre-programming different naïve T cell subsets to exhibit different immune responses post-activation. Collectively, our data and broadly applicable framework defined microRNA regulatory circuits across a variety of naïve CD8 + T cell subsets.

  PublisherOA PDFDOI

• Pervasive <i>cis</i> -regulatory co-option of a transposable element family reinforces cell identity across the mouse immune system

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-25

  articleOpen accessSenior authorCorresponding

  -regulatory contribution of TEs to immune cell development is less characterized. Here, we analyzed hundreds of chromatin accessibility, gene expression, transcription factor occupancy and DNA-DNA contact datasets in diverse mouse and human immune cells. We identified two rodent-specific TE subfamilies, ORR1E and ORR1D2 (collectively, ODE) that have transformed into cell type-specific enhancers across the mouse immune system. ODE loci acquired mutations post-insertion that enable differential binding of lineage-specifying transcription factors. ODEs show evidence of evolutionary sequence constraint and contact promoters of hundreds of genes in immune cells. ODE-targeted genes show cell type-specific and mouse-specific increases in expression compared to concordant human cell types. Thus, a single TE family can undergo functionalization after its genomic spread to generate batteries of cell-specific enhancers supporting a complex developmental cascade.

  PublisherOA PDFDOI

• Gene-regulatory programs that specify age-related differences during thymocyte development

  Cell Reports · 2025-06-25 · 2 citations

  articleOpen accessSenior author

  T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene-regulatory programs and their link to age-related differences. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern the effector response and cell cycle. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing readout, to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. In summary, our study defines gene-regulatory programs that regulate age-specific differences in T cell development.

  PublisherOA PDFDOI

• Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

  medRxiv · 2025-04-16 · 7 citations

  preprintOpen access

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep. The disease mechanism of ME/CFS is unknown, with no effective curative treatments. In this study, we present a multi-site ME/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME/CFS based on personal rare variants, but also links genetic risk to various ME/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations. Transcriptome and network analyses highlight the functional importance of these genes across a wide range of tissues and cell types, including the central nervous system (CNS) and immune cells. Patient-derived multi-omics data implicate reduced expression of ME/CFS risk genes within ME/CFS patients, including in the plasma proteome, and the transcriptomes of B and T cells, especially cytotoxic CD4 T cells, supporting their disease relevance. Pan-phenotype analysis of ME/CFS genes further reveals the genetic correlation between ME/CFS and other complex diseases and traits, including depression and long COVID-19. Overall, HEAL2 provides a candidate genetic-based diagnostic tool for ME/CFS, and our findings contribute to a comprehensive understanding of the genetic, molecular, and cellular basis of ME/CFS, yielding novel insights into therapeutic targets. Our deep learning model also offers a potent, broadly applicable framework for parallel rare variant analysis and genetic prediction for other complex diseases and traits.

  PublisherOA PDFDOI

• Author Reply to Peer Reviews of Argonaute proteins regulate the timing of the spermatogenic transcriptional program

  2025-06-10

  peer-review
  PublisherDOI

• Single-cell multiomics reveals the distinct properties of neonatal and adult recent thymic emigrants

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-01

  preprintOpen access

  Abstract Following thymic egress, CD8+ T cells must undergo a post-thymic maturation process to transition from a recent thymic emigrant (RTE) to a mature naïve T cell. Since the neonatal T cell pool is comprised of significantly more RTEs, the prevailing notion is that neonatal CD8+ T cells behave differently than their adult counterparts simply because they have undergone less post-thymic maturation. To test this theory, we leveraged a fate mapping mouse model and paired single cell transcriptome and TCR sequencing to compare neonatal and adult CD8+ RTEs that have undergone the same amount of post-thymic maturation. Interestingly, we found that neonatal and adult CD8+ RTEs exhibit distinct phenotypes, gene expression profiles, TCR usage, and functions. These data suggest that neonatal CD8+ T cells are not simply immature adult CD8+ T cells and that age-related changes in CD8+ T cell functions in early life cannot be attributed solely to differences in the amount of post-thymic maturation.

  PublisherOA PDFDOI

Recent grants

• NIH Grant P50HD076210

  NIH · $14.7M · 2021

• The developmental layers in the CD8+ T cell response to chronic infection

  NIH · $4.1M · 2014–2024

• Roles for DevelopmentallyRegulated microRNAs in Neonatal Immunity

  NIH · $2.2M · 2017–2022

• Identifying cis and trans factors required for microRNA function

  NIH · $1.5M · 2013–2019

Frequent coauthors

• David P. Bartel

  Whitehead Institute for Biomedical Research

  47 shared

• Elizabeth A. Fogarty

  University of Sheffield

  38 shared

• Raimundo Freire

  Universidad de La Laguna

  36 shared

• Kyle Kai‐How Farh

  Illumina (United States)

  34 shared

• Wendy K. Johnston

  Howard Hughes Medical Institute

  34 shared

• Lee P. Lim

  29 shared

• Jennifer K. Grenier

  Cornell University

  28 shared

• Paula E. Cohen

  Cornell University

  25 shared

Awards & honors

• A&S honors 13 faculty with endowed professorships