publications

2024

1. Quantifying Functional Conservation of Human and Mouse Regulatory Elements via FUNCODE

   Weixiang Fang, Chaoran Chen, Boyang Zhang, and 4 more authors

   bioRxiv 2024

   Abs

   Evolutionary conservation is crucial for understanding genome functions and lays the foundation for using animal models in studying human diseases. However, conventional conservation scores based on DNA sequence evolution do not capture the dynamic biochemical activities of DNA elements, termed functional conservation. Quantifying functional conservation has been limited by the availability of functional genomic data matched across species. To address this, we developed FUNCODE, a framework for characterizing functional conservation through in silico sample matching. Applying FUNCODE to 2,595 uniformly processed datasets from the Encyclopedia of DNA Elements (ENCODE), we generated genome-wide FUNCODE scores for human and mouse regulatory elements, identifying 3.3 million functionally conserved human-mouse element pairs. We demonstrate FUNCODE’s diverse applications, including annotating 78,501 novel regulatory elements, transferring 37,968 high-resolution human ENCODE Hi-C loops in immune lineages to mice, identifying conserved functional signals for disease modeling, and enhancing cross-species integration of single-cell omics data.Competing Interest StatementThe authors have declared no competing interest.

2. A consensus variant-to-function score to functionally prioritize variants for disease

   Tabassum Fabiha, Ivy Evergreen, Soumya Kundu, and 23 more authors

   bioRxiv 2024

   Abs

   Identifying and functionally characterizing causal disease variants in genome-wide association studies remains a pressing challenge. Here, we construct a consensus variant-to-function (cV2F) score that assigns a single value to each common single-nucleotide variant in the genome, and helps to predict and characterize causal disease variants. The cV2F score leverages features reflecting variant-level experimentally and computationally predicted function (e.g. allelic imbalance and sequence-based deep learning models) and element-level function (e.g. predicted enhancers), and learns optimal combinations of features by training a gradient boosting model on GWAS fine-mapping results. The cV2F-annotated variants attained an AUPRC of 0.822 at identifying held-out fine-mapped variants. Variants with high cV2F scores are highly enriched for heritability (14.2x, s.e. 0.5) across 66 diseases/traits, are uniquely informative for disease heritability, and are highly predictive of variants implicated by reporter assays; cV2F substantially outperforms previous variant-to-function scores using all of these metrics. GWAS fine-mapping of 110 diseases/traits informed by cV2F identified 14.3% more confidently fine-mapped (PIP > 0.95) variants than non-functionally informed fine-mapping. We further constructed tissue/cell line-specific cV2F scores that prioritize variants based on regulatory potential in specific tissues/cell lines, attaining high heritability enrichment for tissue-related diseases/traits (15.6x, s.e. 2.3) while providing independent information (average correlation of 0.27 with the primary cV2F score). We highlight examples of GWAS loci for which cV2F pinpoints causal variants with high confidence and elucidates their functional role.Competing Interest StatementThe authors have declared no competing interest.

3. Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate

   Jesse S Handler, Zijie Li, Rachel K Dveirin, and 4 more authors

   bioRxiv 2024

   Abs

   Identifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relative in vivo metastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targets Fos and Il23a, and beyond the IL-1 pathway including Myo1b and Tmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.Competing Interest StatementJ.H. and R.K. are listed as co-inventors on a provisional patent on the use of this studies finding for clinical diagnoses. E.J.F serves on the Scientific Advisory Board of Resistance Bio, as a consultant for Mestag Therapeutics and Merck, and receives research funding from Abbvie Inc and Roche/Genetech outside the scope of this work.

4. Reconstructing progenitor state hierarchy and dynamics using lineage barcode data

   Weixiang Fang, Yi Yang, Hongkai Ji, and 1 more author

   2024

2023

1. High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells

   Weifeng Li, Cynthia Berlinicke, Yinyin Huang, and 8 more authors

   Iscience 2023
2. Regional gene expression in the retina, optic nerve head, and optic nerve of mice with optic nerve crush and experimental glaucoma

   Casey J Keuthan, Julie A Schaub, Meihan Wei, and 7 more authors

   International journal of molecular sciences 2023

2022

1. Quantitative fate mapping: A general framework for analyzing progenitor state dynamics via retrospective lineage barcoding

   Weixiang Fang, Claire M Bell, Abel Sapirstein, and 5 more authors

   Cell 2022

2021

1. Single-cell transcriptomic reveals molecular diversity and developmental heterogeneity of human stem cell-derived oligodendrocyte lineage cells

   Xitiz Chamling, Alyssa Kallman, Weixiang Fang, and 8 more authors

   Nature communications 2021

2019

1. Global prediction of chromatin accessibility using small-cell-number and single-cell RNA-seq

   Weiqiang Zhou, Zhicheng Ji, Weixiang Fang, and 1 more author

   Nucleic acids research 2019