Biology subjects

Cornejo, P.

Publications and source records attributed to Cornejo, P..

3 recordsLinked to original sources

bioRxiv2024

DNA-Diffusion: Leveraging Generative Models for Controlling Chromatin Accessibility and Gene Expression via Synthetic Regulatory Elements

The challenge of systematically modifying and optimizing regulatory elements for precise gene expression control is central to modern genomics and synthetic biology. Advancements in generative AI have paved the way for designing synthetic sequences with the aim of safely and accurately modulating gene expression. We leverage diffusion models to design context-specific DNA regulatory sequences, which hold significant potential toward enabling novel therapeutic applications requiring precise modulation of gene expression. Our framework uses a cell type-specific diffusion model to generate synthetic 200 bp regulatory elements based on chromatin accessibility across different cell types. We evaluate the generated sequences based on key metrics to ensure they retain properties of endogenous sequences: transcription factor binding site composition, potential for cell type-specific chromatin accessibility, and capacity for sequences generated by DNA diffusion to activate gene expression in different cell contexts using state-of-the-art prediction models. Our results demonstrate the ability to robustly generate DNA sequences with cell type-specific regulatory potential. DNA-Diffusion paves the way for revolutionizing a regulatory modulation approach to mammalian synthetic biology and precision gene therapy.

synthetic biology↗

bioRxiv2024

A Bag-Of-Motif Model Captures Cell States at Distal Regulatory Sequences

Deciphering the intricate regulatory code governing cell-type-specific gene expression is a fundamental goal in genetics. Current methods struggle to capture the complex interplay between gene distal regulatory sequences and cell context. We developed a computational approach, BOM (Bag-of-Motifs), which represents cis-regulatory sequences by the type and number of TF binding motifs it contains, irrespective of motif order, orientation, and spacing. This simple yet powerful representation allows BOM to efficiently capture the complexity of cell-type-specific information encoded within these sequences. We apply BOM to mouse, human, and zebrafish distal regulatory regions, demonstrating remarkable accuracy. Notably, the method outperforms more complex deep learning models at the same task using fewer parameters. BOM can also uncover cross-species sequence similarities unrecognized by genome alignments. We experimentally validate our in silico predictions using enhancer reporter assay, showing that motifs with the most significant explanatory power are sequence determinants of cell-type specific enhancer activity. BOM offers a novel systematic framework for studying cell-type or condition-specific cis-regulatory sequences. Using BOM, we demonstrate the existence of a highly predictive sequence code at distal regulatory regions in mammals driven by TF binding motifs.

bioinformatics↗

bioRxiv2023

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts and TF binding profiles in HSPC subsets (HSC, CMP, GMP, MEP) and found that heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific heptad-TF combinations play critical roles in regulating hematopoietic differentiation and provide a valuable resource for development of targeted therapies to manipulate specific HSPC subsets.

developmental biology↗