The Laboratory of Molecular Growth Regulation conducts research on the control of cell proliferation, DNA replication, and gene regulation in eukaryotic cells. With respect to the last, independent groups work in complementary areas, including gene regulation of the developing immune system, control of gene expression during early embryogenesis, chromatin-mediated gene silencing, and transcription of small RNA-encoding genes. Of particular interest with respect to immune system function are transcription factors that control cell proliferation and differentiation. Studies by Keiko Ozato and her coworkers on ICSBP/IRF-8 have revealed that this transcription factor is essential for the proper development of macrophages, granulocytes, and dendritic cells. Defects in these cell lineages can be rescued by introduction of the ICSBP gene into cells derived from knock-out mice. Recent work has focused on the identification of critical target genes controlled by ICSBP. One such target gene, IL12-p40, is a cytokine that plays an essential role in the development of innate immunity. Microarray studies have revealed at least 50 additional gene products whose expression is up- or down-regulated by ICSBP. Ozato and her colleagues have shown that both ICSBP and Brd4, another transcription factor under investigation, function in part by regulating the activity of chromatin. Melvin DePamphilis is leading a series of investigations into gene regulation during early mouse embryogenesis involving the transcription factor mTEAD-2. Interestingly, a number of promoters and enhancers become responsive to mTEAD-2 concomitant with the onset of zygotic gene expression. Recent studies have led to the identification of YAP65 as a long sought-after co-activator of the TEAD family of transcription factors. YAP65, which also binds to Src/Yes protein kinases and interacts with the cytoplasmic localization protein 14-3-3, is a strong candidate for the transducer of mitogenic signals that activate TEAD-dependent transcription. Richard Maraia directs studies focusing on the multifunctional factor known as human La antigen. La has been characterized as a regulatory chaperone for nascent RNAs. Work in this laboratory has been instrumental in defining the precise roles of La in the nuclear trafficking and processing of associated tRNAs. Related studies have highlighted the regulatory function of a major phosphorylation site in the La antigen. In this case, phosphorylation modulates the interaction of La with nascent transcripts as well as its trafficking within the nucleus. Given that these studies have revealed that the protein contains an efficient carrier-mediated nuclear export signal, the chaperone function of La appears also to include export to the cytoplasm. Finally, a major area of interest for the laboratory concerns higher-order chromatin structure, in particular how defects in the maintenance of such structures may underlie developmental disorders and age-related diseases. Under the direction of Bruce Howard, the researchers have developed random sampling approaches to facilitate the mapping of chromatin structures across the genome and to enable them to detect areas of chromatin remodeling. In related work, they have linked a form of chromatin-mediated gene expression control, termed imprinting, to histone H3 methylation.