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Muscleblind-like proteins are novel modulators of the tumor-immune microenvironment

ABSTRACT: Exploiting the immune system to target and eradicate cancer cells is an area of intense clinical study. However, the underlying mechanisms that shape the tumor-immune microenvironment remain poorly understood. Here, we identify Muscleblind-like (MBNL) proteins as novel modulators of the tumor microenvironment across diverse cancer types. Initially, in a mouse melanoma model, we demonstrate that loss of MBNL expression drives reduced cytotoxic CD8+ T cell tumor infiltrate and increased tumor cell viability. This causes an attenuated response to inflammatory stimulation with interferon gamma and concomitantly reduced antigen presentation by MHC Class I. We then extended these studies to 29 human cancer types from extensive analysis of TCGA to find that high MBNL1 expression was consistently associated with augmented cytotoxic T cell tumor infiltration. These new insights position MBNL proteins as critical players shaping the immune landscape across diverse malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE261415 | GEO | 2025/03/10

REPOSITORIES: GEO

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Transcriptome-wide Regulation of Splicing and mRNA Localization by Muscleblind Proteins

Project description:The Muscleblind-like (Mbnl) family of RNA-binding proteins plays important roles in muscle and eye development and in Myotonic Dystrophy (DM), where expanded CUG or CCUG repeats functionally deplete Mbnl proteins. We identified transcriptome-wide functional and biophysical targets of Mbnl proteins in brain, heart, muscle, and myoblasts using RNA sequencing and crosslinking/immunoprecipitation-sequencing approaches. This analysis identified several hundred splicing events whose regulation depended on Mbnl function, in a pattern indicative of functional interchangeability between Mbnl1 and Mbnl2. A nucleotide resolution RNA map associated repression or activation of exon splicing with Mbnl binding near either 3' splice site or near the downstream 5' splice site, respectively. Transcriptomic analysis of sub-cellular compartments uncovered a global role for Mbnls in regulating localization of mRNAs encoding membrane, synaptic and other proteins in both mouse and Drosophila cells, and Mbnls also contribute to protein secretion. These findings hold several new implications for DM pathogenesis. To assess global functions of Muscleblind proteins, RNA-Seq was performed using WT and Mbnl1 KO brain, heart, and muscle (5 mice each). Additionally, C2C12 mouse myoblasts were depleted of Mbnl1, Mbnl2, or both. Subcellular fractionation experiments were performed to analyze mRNA localization following depletion of Mbnl1 and Mbnl2 in C2C12 mouse myoblasts, and following depletion of Mbnl in Drosophila S-2R+ cells. CLIP-Seq was also performed against Mbnl1 in mouse brain, heart, muscle, and C2C12 myoblasts. Finally, ribosome footprinting was performed with C2C12 mouse myoblasts that were depleted of Mbnl1, Mbnl2, or both.

2012-08-17 | E-GEOD-39911 | biostudies-arrayexpress

Muscleblind-like compound knockout models for myotonic dystrophy

Project description:Myotonic dystrophy (DM) is a multi-systemic disease that severely impacts cardiac and skeletal muscle functions as well as the central nervous system. DM is unusual because it is RNA-mediated disease due to the expression of C(C)UG expansion RNAs that inhibit the activities of the muscleblind-like (MBNL) proteins. In mice, studies using Mbnl1 and Mbnl2 single knockouts have revealed that Mbnl1 plays a predominant role in skeletal and heart muscle alternative splicing regulation while Mbnl2 performs an analogous splicing function in the brain. However, Mbnl single knockout models fail to recapitulate the full-range of adult-onset DM muscle symptoms. Here, we report that Mbnl1; Mbnl2 double knockouts are embryonic lethal while Mbnl1-/-; Mbnl2+/- mice, which express no Mbnl1 and reduced levels of Mbnl2, are viable but develop cardinal features of adult-onset DM cardiac and skeletal muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in both Mbnl1-/- and Mbnl1-/-; Mbnl2+/- knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the MBNL loss-of-function model for DM and provide novel Mbnl compound knockout models to investigate the molecular pathways disrupted by RNA-mediated disease. Mbnl2 protein-RNA interactions were assessed in 4-month-old WT and Mbnl1-/- quadriceps muscles in triplicates by HITS-CLIP.

2013-12-01 | E-GEOD-47794 | biostudies-arrayexpress

Compound loss of muscleblind-like function in myotonic dystrophy

2013-12-01 | GSE47794 | GEO

Transcriptome-wide Regulation of Splicing and mRNA Localization by Muscleblind Proteins

2012-08-17 | GSE39911 | GEO

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming I

Project description:Previous investigations of the core gene regulatory circuitry that controls embryonic stem cell (ESC) pluripotency have largely focused on the roles of transcription, chromatin and non- coding RNA regulators. Alternative splicing (AS) represents a widely acting mode of gene regulation, yet its role in the regulation of ESC pluripotency and differentiation is poorly understood. Here, we identify the Muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of AS events that are differentially regulated between ESCs and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ESC-like AS pattern for at least half of these AS events. Among the events is an ESC-specific AS switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells (iPSCs) during somatic cell reprogramming. mRNA profiles of various embryonic stem cells, tissues and cell lines from human and mouse using high-throughput sequencing data and the role of MBNL proteins in regulation of ESC-differential alternative splicing

2013-06-26 | E-GEOD-45503 | biostudies-arrayexpress

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming II

2013-06-26 | E-GEOD-45504 | biostudies-arrayexpress

Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes

Project description:RNA transport and local translation provide spatial control of gene expression, and RNA binding proteins (RBPs) act as critical adapters in this multi-step process. Muscleblind-like (MBNL) RNA binding proteins, implicated in Myotonic Dystrophy and cancer, localize RNAs to myoblast membranes and distal neurites, through unknown mechanisms. We found that MBNLs form motile and anchored granules in neurons and myoblasts, and selectively associate with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs also associate with these kinesins, implicating a motor-RBP specificity code. Live cell imaging and fractionation revealed that membrane anchoring is mediated through the unstructured carboxy-terminal tail of MBNL1. Both kinesin- and membrane-recruitment functions were reconstituted using MBNL-MS2 coat protein fusions; this approach, termed RBP Module Recruitment and Imaging (RBP-MRI), decouples RNA binding, kinesin recruitment, and membrane anchoring functions, while also establishing general strategies for studying multi-functional, modular domains of RBPs.

2022-07-09 | GSE207597 | GEO

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming I

2013-06-26 | GSE45503 | GEO

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming II

2013-06-26 | GSE45504 | GEO

Increased Muscleblind levels by chloroquine treatment improves myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

Project description:Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3'UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately originates phenotypes. In this work we demonstrate that treatment with the anti-autophagic drug chloroquine in Drosophila and mouse (HSALR) models, and patient-derived myoblasts, was sufficient to upregulate MBNL1 and 2 proteins. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine rescued locomotion and average crossectional muscle area, and extended median survival of DM1 flies. In HSALR mice the drug recovered muscular strength and histopathology signs, and reduced myotonia grade. Taken together these results offer a novel means to replenish the critically low levels of MBNLs in DM1.

2019-11-22 | GSE128844 | GEO

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