Anti-BRD3 monoclonal antibody, clone 8H7

Preterm birth is a global healthcare challenge. Spontaneous preterm birth (sPTB) is commonly caused by inflammation, yet there are currently no effective therapies available. The 3 Bromodomain and Extra-Terminal motif (BET) proteins, Bromodomain-containing protein (Brd) 2 (Brd2), Brd3 and Brd4 regulate inflammation in non-gestational tissues. The roles of Brd2-4 in human pregnancy are unknown. Using human and mouse models, the present study has identified the Brd proteins part of the process by which inflammation induces parturition. Using human clinical samples, we demonstrate that labor and infection increase the expression of Brds in the uterus and fetal membranes. In primary human myometrial, amnion and decidual cells, we found that global Brd protein inhibition, as well as selective inhibition of Brds, suppressed inflammation-induced expression of mediators involved in myometrial contractions and rupture of fetal membranes. Importantly, studies in the mouse model demonstrate that the pan-Brd inhibitor JQ1 reduced intrauterine inflammation induced by bacterial endotoxin 2 LPS as well as decreasing the effectiveness of LPS to induce parturition. These results implicate BET proteins as novel therapeutic targets for reducing inflammation associated with spontaneous preterm labor.

A hallmark of retroviral replication is integration of the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in gene therapeutic trials, caused by activation of proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) and MLV integrase specifically interact and colocalize within the nucleus of the cell. Inhibition of the BET proteins' chromatin interaction via specific bromodomain inhibitors blocks MLV virus replication at the integration step. MLV integration site distribution parallels the chromatin binding profile of BET proteins, and expression of an artificial fusion protein of the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75 retargets MLV integration away from transcription start sites and into the body of actively transcribed genes, conforming to the HIV integration pattern. Together, these data validate BET proteins as MLV integration targeting factors.