Structural dynamics of the breast cancer genome in response to hormones
Speaker: Miguel Beato, MD, Ph.D Centre de Regulació Genòmica (CRG). Barcelona, Spain
Organizers: IRB Barcelona
Date: Friday, February 12, 2017 12:00h
Place: Fèlix Serratosa, Parc Científic de Barcelona, Spain
Host: Dr.Salvador Aznar Benitah, IRB Barcelona
Eukaryotic cells decode environmental information via receptors and signalling networks that converge in the cell nucleus to adjust an integrated gene expression response. We study the response of breast cancer cells to the steroid hormones estrogens and progesterone (Pg) acting via their respective receptors (ER and PR, respectively) to decipher the underlying molecular mechanisms.
The organization in nucleosomes of the DNA sequences recognized by PR is a requisite for receptor binding and the initiation of chromatin remodelling leading to displacement of histones H1 and H2A/H2B by receptor-associated enzymes, including histone modifying enzymes and ATP-dependent chromatin remodelers, as well as activated PARP1, which synthesize large amounts of Poly-ADP-Ribose (PAR). These epigenetic processes are required for the rapid regulation of thousands of genes leading to cell proliferation. In addition to nucleosomes, higher levels of genome organization also participate in hormone action. The conserved partition of the genome in consecutive topological associating domains (TADs) contributes to coordination of the hormonal response. Hormone regulated genes tend to segregate into TADs that respond as a whole with either activation or repression of transcription.
The extensive chromatin remodelling in response to hormones requires large amounts of energy. A fraction of the ADPR derived from PAR degradation is converted to ATP in the nucleus by NUDIX5 in the presence of PPi. NUDIX5 is known to catalyse the hydrolysis of ADPR to AMP and R-5-P, but in response to hormone NUDIX5 is dephosphorylated, leading to a conformational change that enables it to catalyse the reaction of ADPR with PPi to generate ATP and R-5-P. This nuclear ATP is essential for chromatin remodelling and gene regulation by estrogens or progesterone, as well as for DNA damage repair. NUDIX5 is overexpressed in breast cancers and is a marker for poor prognosis. Thus, it represents a novel target for breast cancer management.