Biology subjects

Mallory, M. J.

Publications and source records attributed to Mallory, M. J..

4 recordsLinked to original sources

bioRxiv2025

Integrative analysis of RNA binding proteins identifies DDX55 as a novel regulator of 3'UTR isoform diversity

The 3 untranslated regions (3UTRs) of mRNAs play a critical role in controlling gene expression and function because they contain binding sites for microRNAs and RNA binding proteins (RBPs) that alter mRNA stability, localization, and translation. Most mRNA 3 ends contain multiple polyadenylation sites (PAS) that can be utilized in condition-specific manners, a process known as alternative polyadenylation (APA), however the mechanisms driving the regulation of APA remain poorly characterized. By integrating a large set of over 500 RNA binding protein (RBP) depletion and binding experiments across two cell lines generated by the ENCODE consortium, we uncovered a number of RBPs in each cell type whose depletion leads to widespread alteration of 3 UTR patterns. These include not only known regulators of APA, but also many putative novel regulators of 3UTR isoform expression. We focused analysis on the largely unstudied DEAD box RNA helicase, DDX55, and validate its novel role in 3UTR isoform regulation using molecular assays and targeted 3 end sequencing experiments. Our findings identify DDX55 as a new regulator of APA, particularly at PAS that contain features of RNA secondary structure. Our data also suggest additional previously unrecognized regulators of 3 UTR processing and differential stability.

genomics↗

bioRxiv2020

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, specific inhibition of the IAV-induced splicing in several cases also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein that required for efficient splicing of the IAV M transcript in nuclear speckles. Notably, we find that hnRNP K accumulates in nuclear speckles upon IAV infection, which is likely to alter the accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

molecular biology↗

bioRxiv2020

Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia

Most genes associated with Acute Myeloid Leukemia (AML) are mutated in less than 10% of patients, suggesting alternative mechanisms for gene disruption contribute to this disease. Here we find a set of splicing events that disrupt the expression of a subset of AML-associated genes, including EZH2 and ZRSR2, independent of known somatic mutations. Most strikingly, in at least one cohort, aberrant splicing triples the number of patients with a reduction in functional EZH2 as compared to that predicted by somatic mutation of EZH2 alone. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlights the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.

genomics↗

bioRxiv2017

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic co-regulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these co-regulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, and Drosophila suggests this antagonism is conserved through evolution.

genomics↗