Impact of NSD1 Alternative Transcripts in Actin Filament Formation and Cellular Division Pathways in Fibroblasts

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Germline NSD1 variants cause Sotos syndrome; somatic variants are implicated in cancer.
• Three NSD1 RNA isoforms exist in fibroblasts: canonical, AT2 (NSD1 Δ5Δ7), and AT3 (NSD1 Δ19-23 at 5' end).
• The specific molecular roles of individual NSD1 isoforms remain largely unknown.

Purpose of the Study:

• To investigate the distinct molecular functions of different NSD1 RNA isoforms.
• To elucidate the role of NSD1 isoforms in regulating cellular pathways, specifically the actin cytoskeleton.

Main Methods:

• siRNA-mediated knockdown of NSD1 isoforms in fibroblast cell lines (FBs).
• Analysis of protein expression and transcriptome data following isoform suppression.
• Identification of gene targets for specific NSD1 isoforms, including ACTR3B for AT2.

Main Results:

• Demonstrated that ARP3 actin-related protein 3 homolog B (ACTR3B) is a target of the NSD1 AT2 isoform.
• Showed that loss of both canonical NSD1 and AT2 isoforms impairs fibroblast actin cytoskeleton regulation.
• Observed a selective loss of stress fibers in fibroblasts lacking canonical and AT2 NSD1 isoforms.

Conclusions:

• Distinguished the functional roles of different NSD1 isoforms.
• Established an essential role for NSD1 in regulating the actin cytoskeleton and stress fiber formation in fibroblasts.
• Provided novel insights into NSD1's contribution to cellular structure and function.