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Acute myeloid leukemia (AML) cells require BRD9 to regulate MYC gene expression and prevent myeloid differentiation. Selective inhibition of BRD9 using a chemical probe that was validated using a resistant bromodomain-swap allele of BRD9 limits AML cell growth. Here we show that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI−SNF chromatin-remodeling complex to sustain MYC transcription, rapid cell proliferation and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain that selectively suppress the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9 that retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells confers resistance to the antiproliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2 . To our knowledge, our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.

Use of zinc finger nucleases is an established method for gene targeting in zebrafish. Such strategies are efficient in targeting a single gene of interest. Our study attempts to target many Nodal related genes by targeting the Activin Response Element (ARE) through the use of native DNA binding domains tethered to the Fok1 endonuclease. In this light, genes are targeted in a Nodal-dependent manner, and can retain transcript levels sustained by other signaling pathways. This technique holds the potential to be a high throughput means of generating mutations in the regulatory regions of various Nodal responsive genes with the use of one set of constructs.

Maternal care, including by non-biological parents, is important for offspring survival 1 – 8 . Oxytocin 1 , 2 , 9 – 15 , which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress 15 . However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin. Behavioural studies and neural recordings in mice show that virgin mice can acquire maternal behaviour through an oxytocin-dependent mechanism.

Maternal care is profoundly important for mammalian survival, and non-biological parents can express it after experience with infants. One critical molecular signal for maternal behavior is oxytocin, a hormone centrally released by hypothalamic paraventricular nucleus (PVN). Oxytocin enables plasticity within the auditory cortex, a necessary step for responding to infant vocalizations. To determine how this change occurs during natural experience, we continuously monitored homecage behavior of female virgin mice co-housed for days with an experienced mother and litter, synchronized with recordings from virgin PVN cells, including from oxytocin neurons. Mothers engaged virgins in maternal care by ensuring their nest presence, and demonstrated maternal behavior in self-generated pup retrieval episodes. These social interactions activated virgin PVN and gated behaviorally-relevant cortical plasticity for pup vocalizations. Thus rodents can acquire maternal behavior by social transmission, and our results describe a mechanism for adapting brains of adult caregivers to infant needs via endogenous oxytocin. Footnotes * Response to first round of reviewer comments.