Nuclear speckle proteins form intrinsic and MALAT1 -dependent microphases

Area of Science:

• Molecular Biology
• Cell Biology
• Biophysics

Background:

• Nuclear speckles are crucial for pre-mRNA processing, concentrating splicing factors like serine/arginine rich splicing factors (SRSFs) and TDP-43.
• The nanoscale organization and assembly principles of these splicing factors within speckles remain incompletely understood.

Purpose of the Study:

• To investigate the self-assembly mechanisms of splicing factors (SRSFs and TDP-43) within nuclear speckles.
• To elucidate the role of the lncRNA MALAT1 in modulating these assemblies and their structures.

Main Methods:

• Utilized principles of polymer physics to model SRSFs and TDP-43 as block copolymers.
• Investigated spontaneous microphase separation driven by inter-block interactions.
• Analyzed the effect of MALAT1 binding on microphase separation and structure.

Main Results:

• SRSFs and TDP-43 behave as block copolymers, undergoing spontaneous microphase separation into ordered, size-limited assemblies (30-45 nm).
• Nuclear speckle territories are clusters of these nanoscale microphases.
• The lncRNA MALAT1 preferentially binds to SRSF1 microphases, enhancing separation and altering structures.

Conclusions:

• Splicing factor organization in nuclear speckles is driven by block copolymer self-assembly into distinct nanoscale structures.
• Microphase separation provides a mechanism for concentrating splicing factors into functional units.
• MALAT1 acts as a regulator, modulating the structure and function of these assemblies.