About

Michael Levine is the Anthony B. Evnin '62 Professor in Genomics and a Professor of Molecular Biology at Princeton University. His research focuses on how noncoding regions of the genome function to control the differential patterns of gene expression, both spatially and temporally, that define cell behavior. Levine's lab has studied mechanisms responsible for switching genes on and off in the early Drosophila embryo for over 30 years, leading to the characterization of the eve stripe 2 enhancer, short-range repression, and the regulation of long-range enhancer-promoter interactions. Additionally, his research has explored gene networks underlying the development of the sea squirt Ciona intestinalis, a simple protovertebrate, which has led to the identification of rudimentary tissues for key vertebrate innovations such as cranial neural crest, neurogenic placodes, and the second heart field. Levine has held faculty positions at Columbia University and UCSD, served as Head of the Division of Genetics, Genomics and Development at UC Berkeley, and was a Visiting Professor of Zoology at the University of Zurich. He obtained a BA in Genetics from UC Berkeley and a PhD in Molecular Biophysics & Biochemistry from Yale. He was a postdoctoral researcher in Basel, Switzerland, where he co-discovered the homeobox. Levine was elected to the National Academy of Sciences in 1998 and has received numerous awards including the Molecular Biology Award from the National Academy of Sciences, the Wilbur Cross Medal from Yale, and the EG Conklin Medal from the Society of Development Biology.

Research topics

• Biology
• Genetics
• Computational biology

Selected publications

• Cell numbers contribute to cell fate during Ciona cardiopharyngeal mesoderm specification

  Proceedings of the National Academy of Sciences · 2026-01-08

  articleOpen accessCorresponding

  The Ciona heart cell lineage can be accurately traced back to a pair of blastomeres, the B7.5 cells, that form at the 64-cell stage. In addition to the adult heart, the B7.5 cells also contribute to two tail muscle cells in the larva, as well as the muscles that form the siphons for pumping water for feeding. Because of the simplicity of this system, we have a good understanding of how the B7.5 derivatives are specified during development. However, we know less about how the Ciona embryo precisely regulates cell numbers, as well as what effects altering cell numbers will have on development. We found that cell numbers in the B7.5 lineage are controlled by a pulse of transcription of the cell cycle inhibitor Cdkn1.b . Cdkn1.b can be repressed by the paralogs Prdm1-r.a and Prdm1-r.b that are exclusively transcribed in the B7.5 cells at the 112-cell stage. We unexpectedly found that precocious arrest of cell division in the B7.5 cell lineage resulted in a reversion to tail muscle fate, even in cells that can migrate. Our work demonstrates an unexpected connection between the control of cell numbers and cell fate in development.

  PublisherDOI

• Pair-rule-like transcription patterns during neural tube closure in a proto-vertebrate

  Development · 2025-11-11 · 1 citations

  articleOpen accessSenior author

  Neural tube closure (NTC) is a conserved morphogenetic process in chordates in which the neural plate folds and fuses to form a closed neural tube. While the mechanical forces and signaling pathways governing NTC have been characterized in vertebrates, the transcriptional programs coordinating these behaviors remain less understood. Here, we identify a transcriptional circuit involving Lmx1, Cdkn1b and Msx that regulates dorsal midline dynamics during NTC in the tunicate Ciona. High-resolution HCR in situ hybridization reveals that Lmx1 expression is dynamically enriched at the zippering point and advances in a posterior-to-anterior transcription wave, while Msx is downregulated in the same region, marking a transition from early neural patterning to morphogenesis. As closure progresses, Lmx1 and Cdkn1b exhibit complementary, alternating expression at the dorsal midline, resembling a pair-rule-like pattern. Misexpression experiments show that Lmx1 promotes proliferation and autoregulates, whereas Cdkn1b limits proliferation and impedes closure. Single-cell RNA-seq datasets reveal transcriptionally distinct dorsal neural populations enriched for Lmx1 or Cdkn1b. This transcriptional switch coordinates proliferation and fusion during NTC, suggesting a general strategy for regulating epithelial remodeling in animal embryos.

  PublisherOA PDFDOI

• Vostok: A looping factor for the organization of the regulatory genome in the Drosophila brain

  Molecular Cell · 2025-06-01 · 1 citations

  articleCorresponding
  PublisherDOI

• Chronic Rapamycin Prevents Electrophysiological and Morphological Alterations Produced by Conditional Pten Deletion in Mouse Cortex

  Cells · 2025-01-08

  articleOpen access

  Abnormalities in the mammalian target of the rapamycin (mTOR) pathway have been implicated in numerous developmental brain disorders. While the molecular and histological abnormalities have been described, less is known about alterations in membrane and synaptic excitability with chronic changes in the mTOR pathway. In the present study, we used a conditional mouse model with a deletion of the phosphatase and tensin homologue (Pten-/-, a negative regulator of mTOR) from cortical pyramidal neurons (CPNs). Whole-cell patch clamp recordings in ex vivo slices examined the intrinsic and synaptic membrane properties of layer II/III CPNs in normal mice treated with rapamycin for four weeks, and Pten-/- mice with and without chronic treatment with rapamycin. Compared with control mice, CPNs from Pten-/- mice demonstrated increased membrane capacitance and time constant in association with increased neuronal somatic size, reduced neuronal firing, and decreased frequency of spontaneous and miniature inhibitory postsynaptic currents, consistent with decreased pre-synaptic GABA release. Rapamycin treatment for four weeks prevented these changes in Pten-/- mice. CPNs from normal mice chronically treated with rapamycin, compared with CPNs from naïve mice, showed reduced capacitance and time constant, increased input resistance, and changes in inhibitory synaptic inputs, consistent with increased pre-synaptic GABA release. These results support the concept that Pten deletion results in significant changes in inhibitory inputs onto CPNs, and these alterations can be prevented with chronic rapamycin treatment. In addition, normal mice treated with rapamycin also display altered membrane and synaptic properties. These findings have potential implications for the treatment of neurological disorders associated with mTOR pathway dysfunction, such as epilepsy and autism.

  PublisherOA PDFDOI

• A monotonic MM-type algorithm for estimation of nonparametric finite mixture models with dependent marginals

  ArXiv.org · 2025-05-22

  preprintOpen access1st authorCorresponding

  In this manuscript, we consider a finite nonparametric mixture model with non-independent marginal density functions. Dependence between the marginal densities is modeled using a copula device. Until recently, no deterministic algorithms capable of estimating components of such a model have been available. A deterministic algorithm that is capable of this has been proposed in \citet*{levine2024smoothed}. That algorithm seeks to maximize a smoothed nonparametric penalized log-likelihood; it seems to perform well in practice but does not possess the monotonicity property. In this manuscript, we introduce a deterministic MM (Minorization-Maximization) algorithm for estimation of components of this model that is also maximizing a smoothed penalized nonparametric log-likelihood but that is monotonic with respect to this objective functional. Besides the convergence of the objective functional, the convergence of a subsequence of arguments of this functional, generated by this algorithm, is also established. The behavior of this algorithm is illustrated using both simulated datasets as well as a real dataset. The results illustrate performance that is at least comparable to the earlier algorithm of \citet*{levine2024smoothed}. A discussion of the results and possible future research directions make up the last part of the manuscript.

  PublisherOA PDFDOI

• A pair-rule-like transcription network coordinates neural tube closure in a proto-vertebrate

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-24

  preprintOpen accessSenior authorCorresponding

  Abstract Neural tube closure (NTC) is a conserved morphogenetic process in chordates, during which the neural plate folds and fuses to form a closed neural tube. While the mechanical forces and signaling pathways governing NTC have been characterized in vertebrates, the transcriptional programs coordinating cell behaviors during closure remain less understood. Here, we identify a transcriptional circuit involving Lmx1, Cdkn1b , and Msx that regulates dorsal midline dynamics during NTC in the tunicate Ciona . High-resolution HCR in situ hybridization reveals that Lmx1 is dynamically enriched at the zippering point and advances in a posterior-to-anterior transcription wave, while Msx is downregulated in the same region, marking a transition from early neural patterning to morphogenetic execution. As closure progresses, Lmx1 and Cdkn1b exhibit complementary, alternating expression at the dorsal midline, resembling a pair-rule-like pattern. Misexpression studies show that Lmx1 promotes proliferation and activates its own expression, whereas Cdkn1b limits proliferation and impedes closure. Single-cell RNA-seq reveals transcriptionally distinct dorsal neural populations enriched for Lmx1 or Cdkn1b , supporting spatially organized cell-cycle states. These findings suggest that a transcriptional switch from Msx to Lmx1 , followed by spatially alternating Lmx1 and Cdkn1b activity, coordinates proliferation and neural fold fusion during NTC. This mechanism may represent a general strategy for regulating epithelial remodeling in animal embryos.

  PublisherOA PDFDOI

• Metadomain and metaloop genome interactions in mammalian T cells

  Cell Reports · 2025-09-21

  preprintOpen access

  In briefDolsten et al. identify megabase-scale and inter-chromosomal metadomain and metaloop interactions that organize key T cell-specific genes across the genome.Integrating chromosomal organization and regulatory genomics datasets, they reveal distinct interchromosomal hubs, including a superenhancer-enriched hub linked to T cell-specific gene activation, and factors underlying metaloops.

  PublisherOA PDFDOI

• Accelerating Hardware Computational Speed-up of Digital Image Processing Algorithms using Flexible Tunable Multi-NIOS-II Soft Processors on an FPGA: A Centralized Versus a Distributed Solution

  2025-06-12

  article1st authorCorresponding

  These days, there is a big wave of interest in the search for efficient algorithms to solve many problems at the hardware level or embedded systems for measurements and computational intelligence in image processing & understanding in computer vision, as well as the life sciences. There is an interest in hardware architectures showing how FPGAs can compete or perhaps outperform GPUs and CPUs in some applications. Hardware accelerators for a CPU provide power efficiency in the case of FPGAs and computational performance in the case of GPUs with high parallelism. On the one hand, in the case of irregular parallelism, given the latest development in FPGAs, this latter may, in the future, perhaps exhibit superiority over homogeneous parallelism in GPUs. On the other hand, one of the limitations of FPGAs is that they are relatively “hard to program” in an optimized RTL code, which results in a long development time. This paper presents and evaluates a hardware implementation for measurement and application in digital image processing and understanding. We experimentally show the further speed-up obtained by implementing a soft, flexible, and heterogeneous SoC multi-core architecture. This is with some hardware modification via a synchronized varying-size multi-port memory access, with two soft NIOS-II processors, with additional hardware modification, in an FPGA. We experimentally measure the computational performance differences between using a centralized software-programmable SoC approach and a heterogeneous multi-core SoC approach with additional modified hardware. The resulting FPGA system methodology, combining SoC soft and flexible components with additional modified hardware, can be flexibly programmed by combining assembly language, C/C++, and VHDL.

  PublisherDOI

• 3D chromatin structures precede genome activation in Drosophila embryogenesis

  Cell Genomics · 2025-09-17 · 3 citations

  articleOpen access

  3D chromatin structure is critical for the regulation of gene expression during development. Here we used Micro-C assays at 100-bp resolution to map genome organization in Drosophila melanogaster throughout the first half of embryogenesis. These high-resolution contact maps reveal fine-scale features such as loops and boundaries delineating topologically associating domains. Notably, we observe that 3D chromatin structures form prior to zygotic genome activation and persist during successive mitotic cycles. Integrative analysis with 149 public chromatin immunoprecipitation sequencing (ChIP-seq) datasets identifies four classes of chromatin structuring elements, including a distinct group enriched for GAGA-associated factor (GAF) and Zelda binding, associated with developmental-gene regulation. These elements are mitotically retained and exhibit sequence and structure similarity between D. melanogaster and D. virilis. We propose that 3D chromatin organization in the pre-cellular embryo facilitates deployment of developmentally regulated genes during Drosophila embryogenesis.

  PublisherDOI

• Comprehensive Single Molecule View of Transcriptional Dynamics in Development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-29

  preprintOpen accessSenior authorCorresponding

  Abstract Dynamic patterns of gene expression drive animal development. These transcriptional dynamics depend on the interplay of diverse developmental enhancers within complex regulatory landscapes. Here, we employ a single-molecule genomic method, Fiber-Seq, to capture the simultaneous transcriptional and regulatory states of millions of 20-30 kb chromatin fibers in the 2-4hr Drosophila embryo. These snapshots of genes and their surrounding regulatory context reveal that the basic unit of transcription at highly transcribed genes is a convoy of 2-14 tightly spaced polymerases (Pol II). Further, a subset of templates exhibits hyperbursting, whereby most or all nucleosomes are evicted from the gene body facilitating maximum rates of transcription. We demonstrate that hyperbursting is achieved through cooperation of numerous cis-regulatory elements, and that the resulting nucleosome eviction appears to trigger a novel silencer in the ftz 3’ UTR. We anticipate that similar mechanisms are used by vertebrate processes requiring intense transcription like somitogenesis and erythropoiesis.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM046638

  NIH · $4.2M · 2017

• Control of the 4D chromatin landscape underlying gene activity during development

  NIH · $3.2M · 2020–2025

• Heart Morphogenesis in the Ascidian, Ciona Intestinalis

  NSF · $420k · 2005–2008

• Visualization of gene activity in the Drosophila embryo

  NIH · $6.0M · 2016–2026

• Notochord Differentiation in the Ascidian, Ciona Intestinalis

  NSF · $108k · 1996–1997

Frequent coauthors

• Guy L. Steele

  Oracle (United States)

  109 shared

• Laxmikant V. Kalé

  University of Illinois Urbana-Champaign

  84 shared

• Svein Eikeseth

  OsloMet – Oslo Metropolitan University

  76 shared

• Patricia Prelock

  76 shared

• Deborah Fein

  University of Connecticut

  76 shared

• Daniel S. Rokhsar

  Innovative Genomics Institute

  47 shared

• Xinyang Bing

  Thomas Jefferson University

  42 shared

• Jeffrey Glennon

  40 shared

Labs

• Michael Levine's LabPI

Education

• Postdoctoral Research Associate, Department of Biochemistry

  UC Berkeley

  1984

• Postdoctoral Research Associate, Department of Cell Biology

  Der Universitat Basel

  1983

• PhD, Department of Molecular Biophysics & Biochemistry

  Yale University

  1981

• BA, Department of Genetics

  UC Berkeley

  1976

Awards & honors

• Elected to the National Academy of Sciences (1998)
• Molecular Biology Award from the National Academy of Science…
• Wilbur Cross Medal from Yale University (2009)
• EG Conklin Medal from the Society of Development Biology (20…