Human Satellite 3 DNA encodes megabase-scale transcription factor binding platforms

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Eukaryotic genomes feature large satellite DNA arrays, such as Human Satellite 3 (HSat3).
• The functions of many satellite DNAs, including HSat3, are largely unknown, as they are often excluded from genome assemblies.
• HSat3 constitutes the largest satellite DNA arrays in the human genome.

Purpose of the Study:

• To investigate the understudied functions of Human Satellite 3 (HSat3) DNA.
• To identify proteins that bind to HSat3 regions.
• To explore the role of HSat3 in gene regulation and cellular processes.

Main Methods:

• Systematic screening for HSat3 binding proteins.
• Identification of transcription factor motifs within HSat3.
• Cellular imaging and microscopy (including super-resolution).
• Reporter assays, targeted repression, and inducible protein degradation.

Main Results:

• HSat3 contains millions of transcription factor binding motifs.
• Over a dozen transcription factors, including TEAD1-4 from the Hippo pathway, bind to HSat3.
• TEAD recruits YAP to HSat3 regions in a cell-state specific manner.
• HSat3 arrays facilitate YAP/TEAD localization within the nucleolus, boosting RNA Polymerase I activity.

Conclusions:

• Satellite DNA can encode functional transcription factor binding motifs.
• HSat3 plays a role in regulating ribosomal DNA transcription via the Hippo pathway.
• This study defines a significant functional role for large satellite DNA elements in the genome.