HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Cold-shock protein RNA binding motif 3 (RBM3) exhibits significant neuroprotective effects in various models.
• The exact molecular mechanisms governing RBM3's cold-induced expression are not fully understood.
• Identifying regulators of RBM3 is crucial for developing neuroprotective strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying RBM3 cold induction.
• To identify temperature-dependent regulators of RBM3 expression.
• To explore novel therapeutic targets for neuroprotection.

Main Methods:

• Genome-wide CRISPR-Cas9 knockout screen in human iPSC-derived neurons.
• Analysis of RBM3 mRNA and protein levels under varying temperatures.
• Splicing analysis to identify regulatory elements and factors.
• Investigation of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) function.

Main Results:

• RBM3 expression is significantly modulated by splicing factors, notably HNRNPH1.
• Moderate hypothermia represses the inclusion of a specific poison exon in RBM3 mRNA.
• HNRNPH1 mediates cold-dependent exon skipping through thermosensitive interaction with a G-rich motif.
• This process prevents nonsense-mediated decay of RBM3 mRNA.

Conclusions:

• Discovered a novel mechanism for RBM3 cold induction involving HNRNPH1-mediated alternative splicing.
• Identified a temperature-sensitive regulatory element critical for RBM3 expression.
• Provides new molecular targets for enhancing RBM3-mediated neuroprotection.