About

Yicheng Long, Ph.D., is an Assistant Professor of Biochemistry and Biophysics at Weill Cornell Medicine. His lab studies the crosstalk between RNA and chromatin, with a focus on stem cell differentiation and cardiac development. His research includes understanding the molecular mechanisms of RNA-mediated regulation pathways by Polycomb group (PcG) and Trithorax group (TrxG) proteins, RNA-mediated epigenetic regulation of cardiac development, and how epitranscriptomics and epigenetics interconnect.

Research topics

• Biology
• Genetics
• Computational biology
• Cell biology
• Computer Science
• Evolutionary biology
• Geography
• Engineering
• Archaeology

Selected publications

• Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-11

  articleOpen access

  Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.

  PublisherOA PDFDOI

• Macromolecular interactions dictate Polycomb-mediated epigenetic repression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-15

  preprintOpen accessSenior authorCorresponding

  Abstract The dynamic regulation of epigenetic states relies on complex macromolecular interactions. PRC2, the methyltransferase complex responsible for depositing H3K27me3, interacts with distinct accessory proteins to form the mutually exclusive subcomplexes PHF1-PRC2.1, MTF2-PRC2.1, PHF19-PRC2.1, and PRC2.2. The functions of these subcomplexes are unclear and thought to be highly redundant. Here we show that PRC2 subcomplexes have distinct roles in epigenetic repression of lineage-specific genes and stem cell differentiation. Using a human pluripotent stem cell model, we engineered a comprehensive set of separation-of-function mutants to dissect the roles of individual protein-protein and DNA-protein interactions. Our results show that PRC2.1 and PRC2.2 deposit H3K27me3 locus-specifically, resulting in opposing outcomes in cardiomyocyte differentiation. We find that MTF2 stimulates PRC2.1-mediated repression in stem cells and cardiac differentiation through its interaction with DNA and H3K36me3, while PHF19 antagonizes it. Furthermore, MTF2-PRC2.1 maintains normal cardiomyocyte function. Together, these results reveal the importance and specificity of individual macromolecular interactions in Polycomb-mediated epigenetic repression in human stem cells and differentiation. Highlights The PRC2.1 and PRC2.2 subcomplexes have distinct specificities for H3K27me3 deposition The three PCL accessory proteins have distinct functions in regulating the PRC2 core complex, with MTF2 and PHF19 antagonizing each other Interactions between the PCL proteins and the PRC2 core, DNA, and H3K36me3 dictate PRC2 occupancy and activity at developmental genes PRC2.1 and PRC2.2 play opposing roles in stem cell cardiomyocyte differentiation MTF2 plays key functions in regulating differentiation timing and action potential rhythm in cardiomyocytes

  PublisherOA PDFDOI

• Distinct specificity and functions of PRC2 subcomplexes in human stem cells and cardiac differentiation

  Molecular Cell · 2025-08-01 · 1 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Mutations of Splicing Regulator RBM20 in Atrial Fibrillation

  JACC Basic to Translational Science · 2024-02-01 · 3 citations

  editorialOpen accessSenior authorCorresponding

  [Figure: see text]

  PublisherDOI

• Abstract 1887 Substrate Recognition by Two 3' to 5' RNA Polymerases in Dictyostelium discoideum

  Journal of Biological Chemistry · 2024-03-01

  articleOpen access

  Unlike most polymerases that act in the 5′ to 3′ direction, tRNAHis guanylyltransferase (Thg1) synthesizes RNA 3′ to 5′. Thg1 catalyzes an essential reaction during tRNAHis processing by adding a G nucleotide on the 5′ end of the tRNA in most eukaryotes, forming an identity element for aminoacylation of the tRNA. Recent characterization of Thg1 homologs with alternative specificities, known as Thg1-like proteins (TLPs), raises questions about how distinct substrates are recognized by different members of this highly conserved enzyme family. In the slime mold Dictyostelium discoideum (Ddi), DdiThg1 adds G to the 5′ end of cytosolic (cy-) tRNAHis, while DdiTLP2 catalyzes the same reaction, but only with mitochondrial (mt-) tRNAHis substrates. In vivo and in vitro, these two enzymes exhibit strict specificity for their respective tRNA substrates. Moreover, unlike Thg1, DdiTLP2 does not depend on the GUG anticodon for tRNAHis recognition, suggesting different mechanisms for tRNA recognition by these two enzymes. We aimed to determine the molecular basis for the distinct RNA substrate specificities of DdiThg1 and DdiTLP2, and thus to provide insight into the general mechanisms of RNA recognition utilized by distinct 3'-5' RNA polymerases. To answer this question, electrophoretic mobility shift assays (EMSA) were used to assess tRNA binding by DdiThg1 vs. DdiTLP2. These assays revealed no difference in either enzyme's ability to bind to different tRNAs, requiring additional catalytic factors to explain the selective in vitro activities of these enzymes. Sequence comparison was used to identify a unique residue in DdiTLP2 (R187) that is different from an absolutely conserved D/E residue at the analogous position in the rest of Thg1/TLP family members, including in DdiThg1. We hypothesized that this unusual R187 residue may be responsible for the unique biochemical properties exhibited by DdiTLP2. Indeed, replacement of the conserved D residue in DdiThg1 with the R found in DdiTLP2 caused a dramatic reversal of DdiThg1 substrate specificity. The DdiThg1 D150R variant lost the ability to catalyze G-1 addition with cy-tRNAHis and instead gained the ability to act on DdiTLP2's mt-tRNAHis substrate. Interestingly, kinetic and conservative amino acid replacement studies revealed that the change in DdiThg1 predominantly impacts the second step of the 3'-5' addition reaction, suggesting a direct role for the conserved D residue in this nucleotidyl transfer step. This result may also help to explain a previously observed in vivo growth defect associated with alanine replacement of the analogous D residue in Saccharomyces cerevisiae (Sc) Thg1, despite the fact that the ScThg1 D153A variant enzyme retains full in vitro catalytic activity. These results suggest that the DdiThg1 D153/ScThg1 D153 residue helps to control RNA substrate specificity and carry out the nucleotidyl transfer reaction step in this unusual family of 3'-5' RNA polymerases. Grace Johnecheck was supported by NIH T32 GM141955; this research was funded by R01 GM087543.

  PublisherOA PDFDOI

• Application of collaborative filtering in movie recommendation systems and improvements by hyperparameter tuning

  Applied and Computational Engineering · 2024-07-05

  articleOpen access1st authorCorresponding

  In the current era of explosive data growth, accurately recommending movies to users has become a challenge for traditional recommendation algorithms. In this paper, we propose enhancements to the traditional item-based Collaborative Filtering recommendation algorithm by focusing on three aspects: the proportion of the training set and test set, the new similarity algorithm, and the new recall index. These enhancements aim to achieve better recommendation results. We conducted experiments using a movie recommendation system as the testbed and implemented an item-based recommendation algorithm using the Python language. A control experiment was performed using the dataset from the official MovieLens website. The experimental results demonstrate that the improved algorithm exhibits enhanced recommendation accuracy.

  PublisherDOI

• Evaluation of the RNA-dependence of PRC2 binding to chromatin in human pluripotent stem cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-18 · 11 citations

  preprintOpen access1st author

  Polycomb Repressive Complex 2 (PRC2), an important histone modifier and epigenetic repressor, has been known to interact with RNA for almost two decades. In our previous publication (Long, Hwang et al. 2020), we presented data supporting the functional importance of RNA interaction in maintaining PRC2 occupancy on chromatin, using comprehensive approaches including an RNA-binding mutant of PRC2 and an rChIP-seq assay. Recently, concerns have been expressed regarding whether the RNA-binding mutant has impaired histone methyltransferase activity and whether the rChIP-seq assay can potentially generate artifacts. Here we provide new data that support a number of our original findings. First, we found the RNA-binding mutant to be fully capable of maintaining H3K27me3 levels in human induced pluripotent stem cells. The mutant had reduced methyltransferase activity in vitro, but only on some substrates at early time points. Second, we found that our rChIP-seq method gave consistent data across antibodies and cell lines. Third, we further optimized rChIP-seq by using lower concentrations of RNase A and incorporating a catalytically inactive mutant RNase A as a control, as well as using an alternative RNase (RNase T1). The EZH2 rChIP-seq results using the optimized protocols supported our original finding that RNA interaction contributes to the chromatin occupancy of PRC2.

  PublisherOA PDFDOI

• Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation

  Proceedings of the National Academy of Sciences · 2022 · 108 citations

  • Computer Science
  • Biology
  • Computational biology

  Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESC) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spreading of H3K27me3 on the linear genome. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remain unclear. Here, we apply H3K27me3 HiChIP, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes. Genetic deletion of H3K27me3 loop anchors results in disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. In mouse embryos, loop anchor deletion leads to ectopic activation of the partner gene, suggesting that Polycomb-associated loops control gene silencing during development. Further, we find that alterations in PRC2 occupancy resulting from an RNA binding–deficient EZH2 mutant are accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 uses RNA binding to enhance long-range chromosome folding and H3K27me3 spreading. Developmental gene loci have unique roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

  PublisherDOI

• Identification of dangerous driving state based on lightweight deep learning model

  Computers & Electrical Engineering · 2022-11-28 · 19 citations

  articleSenior author
  PublisherDOI

• Targeted mutagenesis in human iPSCs using CRISPR genome-editing tools

  Methods · 2021-01-13 · 5 citations

  articleOpen access1st author
  PublisherOA PDFDOI

Recent grants

• Regulation of a chromatin modifier (Polycomb Repressive Complex 2) by nucleic acids interactions

  NIH · $133k · 2020–2022

Frequent coauthors

• Thomas R. Cech

  University of Colorado Boulder

  31 shared

• Anne R. Gooding

  University of Colorado Boulder

  19 shared

• Tadeusz Dąbroś

  Natural Resources Canada

  17 shared

• Xueyin Wang

  Shandong Provincial QianFoShan Hospital

  12 shared

• Hassan Hamza

  11 shared

• Karen J. Goodrich

  University of Colorado Boulder

  11 shared

• Taeyoung Hwang

  Johns Hopkins University

  10 shared

• Richard D. Paucek

  University of Colorado Boulder

  8 shared

Labs

• Yicheng Long labPI

Education

• Ph.D., Biochemistry Program

  Ohio State University

  2015

• B.S., Department of Biological Sciences and Biotechnology

  Tsinghua University

  2009