Biology subjects

Metzl-Raz, E.

Publications and source records attributed to Metzl-Raz, E..

4 recordsLinked to original sources

bioRxiv2025

Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation

Defining temporal gene regulatory programs driving human organogenesis is essential for understanding congenital defects. We combined a time-resolved, single-cell multi-omic atlas of human induced pluripotent stem cell-derived cardiac organoids with deep learning models of chromatin accessibility, enabling systematic discovery of cis-regulatory syntax underlying heart development and disease. This framework identified cell-state-specific motif syntax, linked motif instances to candidate target genes, and resolved programs governing lineage divergence. Integrating cell-state-resolved molecular profiles with computationally predicted variant effects from congenital heart disease (CHD) cases enabled the prioritization of noncoding variants predicted to disrupt developmental transitions, supporting the paradigm that disease etiology derives from perturbations to regulatory networks governing cardiogenesis. Experimental validation demonstrated that an intronic ANGPTL2 variant altered differentiation outcomes, implicating ANGPTL2 in CHD. This study bridges developmental regulation with disease genetics, establishing a framework for discovering the genetic and molecular basis of congenital disorders.

genetics↗

bioRxiv2024

Histone deacetylase inhibition expands cellular proteostasis repertoires to enhance neuronal stress resilience

Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. The maintenance of proteostasis and membrane protein trafficking is essential for neuronal function throughout development and aging. Cellular stressors, including endoplasmic reticulum (ER) protein folding stress and endosomal membrane trafficking stress, accumulate as neurons age and correlate with age-dependent neurodegeneration. However, how neurons coordinate stress responses across diverse cellular perturbations remains poorly understood. Here we demonstrate that histone deacetylases (HDACs) constrain the flexibility of neurons to engage distinct molecular pathways in response to different types of stress. Genetic or pharmacological inhibition of class I HDACs enhances neuronal resilience to both ER protein folding stress and endosomal membrane trafficking stress in C. elegans and mammalian neurons. RNA sequencing analyses in C. elegans, mouse, and human iPSC-derived neurons reveal that HDAC inhibition makes neurons more developmentally plastic and induces a permissive transcriptional state that likely represents partial cell fate reprogramming. These transcriptomic changes enable neurons to activate latent proteostasis pathways tailored to the specific nature of the stress. Given the growing excitement around partial reprogramming as a strategy to reset the epigenetic clock, our findings establish a direct link between epigenetic modulation and the neuronal stress response, pointing to new therapeutic strategies for enhancing neuronal resilience in aging and disease.

neuroscience↗

bioRxiv2019

Gene transcription as a limiting factor in protein production and cell growth

Growth rate and cell size are principle characteristics of proliferating cells, whose values depend on cellular biosynthetic processes in a way poorly understood. Protein production is critical for growth, and we therefore examined for processes limiting this production. Burdening cells with an excess of inert protein changed endogenous gene expression similarly to transcription-perturbing mutants, was epistatic to these mutants, but did not deplete respective factors from gene promoters. Mathematical modeling, corroborated by experiments, attributed this signature to a feedback which proportionally increases all endogenous gene expression, but lags at fast initiating genes already transcribed close to the maximal possible rate. As a possible benefit of maximizing transcription rates, we discuss a conflict between cell growth rate and size, which emerges above a critical cell size set by transcript abundance. We propose that biochemical limits on protein and mRNA production define the characteristic values of cell size and division time.

cell biology↗

bioRxiv2017

Principles Of Cellular Resource Allocation Revealed By Condition-Dependent Proteome Profiling

Growing cells coordinate protein translation with metabolic rates. Central to this coordination is ribosome production. Ribosomes drive cell growth, but translation of ribosomal proteins competes with production of other proteins. Theory shows that cell growth is maximized when all expressed ribosomes are constantly translating. To examine whether budding yeast function at this limit of full ribosomal usage, we profiled the proteomes of cells growing in different environments. We find that cells produce an excess of ribosomal proteins, amounting to a constant {approx}8% of the proteome. Accordingly, {approx}25% of ribosomal proteins expressed in rapidly growing cells do not contribute to translation. This fraction increases as growth rate decreases. These excess ribosomal proteins are employed during nutrient upshift or when forcing unneeded expression. We suggest that steadily growing cells prepare for conditions that demand increased translation by producing excess ribosomes, at the expense of lower steady-state growth rate.

cell biology↗