Crosstalk between paralogs and isoforms influences p63-dependent regulatory element activity

Area of Science:

• Molecular Biology
• Genetics
• Gene Regulation

Background:

• The p53 family (p53, p63, p73) are crucial transcription factors involved in tumor suppression and development.
• Understanding how p63 regulates gene expression, particularly its dual role in activation and repression, is not well understood.
• Crosstalk between highly similar transcription factors can significantly alter gene regulatory outcomes.

Purpose of the Study:

• To investigate how local DNA sequence context influences p63-dependent transcriptional activity.
• To elucidate the mechanisms controlling p63-mediated gene regulation.
• To understand the impact of transcription factor paralogs and isoforms on gene regulatory element activity.

Main Methods:

• Massively parallel reporter assays (MPRA) were employed to assess p63-dependent transcriptional activity.
• Analysis of p63 response element (p63RE) sequence content and co-enrichment with other transcription factors.
• Investigation of the effects of different p63 isoforms on regulatory element activity.

Main Results:

• Most p63REs activate transcription, with p53 binding contributing significantly to this activity.
• p63RE sequence composition and co-factor enrichment correlate with differential p63-mediated activities.
• p63 isoforms substantially alter transcriptional behavior, activating previously inactive regulatory elements.

Conclusions:

• Local DNA sequence and cellular context critically influence p63-dependent gene regulation.
• Transcription factor paralogs and isoforms play a key role in modulating gene regulatory element activity.
• This study provides novel insights into the complex mechanisms governing p63 function.