BRD4 sustains p63 transcriptional program in keratinocytes

Area of Science:

• Epigenetics and molecular biology
• Cellular biology
• Dermatology

Background:

• Bromodomain-containing protein 4 (BRD4) is an epigenetic modulator crucial for transcription.
• p63 is essential for epithelial development and skin homeostasis.
• The role of BRD4 and Bromodomain and Extra Terminal (BET) inhibitors in non-transformed cells like keratinocytes is largely unknown.

Purpose of the Study:

• To investigate the interaction between BRD4 and p63.
• To explore the functional consequences of this interaction in keratinocytes.
• To understand the therapeutic potential of BRD4 inhibitors in skin disorders.

Main Methods:

• Protein-protein interaction assays
• Functional analyses (depletion studies, inhibitor treatment)
• Transcriptomic analyses (RNA-seq)
• Chromatin immunoprecipitation (ChIP)
• RT-qPCR

Main Results:

• BRD4 physically interacts with p63, p73, and p53, indicating a shared binding region.
• Depletion of p63 or BRD4, or treatment with the BRD4 inhibitor JQ1, alters keratinocyte proliferation and differentiation.
• p63 and BRD4 act synergistically to regulate key keratinocyte-specific genes (e.g., HK2, FOXM1, EVPL).

Conclusions:

• BRD4 plays a significant role in maintaining keratinocyte functions.
• BRD4 and p63 have a complex, synergistic relationship in regulating epithelial gene expression.
• BRD4 inhibitors may hold therapeutic potential for skin disorders.