Summary Elucidation of endogenous cellular protein-protein interactions and their networks is most desirable for biological studies. Here we report our study of endogenous human coregulator protein complex networks obtained from integrative mass spectrometry-based analysis of 3,290 affinity purifications. By preserving weak protein interactions during complex isolation and utilizing high levels of reciprocity in the large dataset we identified many unreported protein associations, such as a transcriptional network formed by ZMYND8, ZNF687 and ZNF592. Furthermore, our work revealed a tiered interplay within networks that share common proteins, providing a conceptual organization of a cellular proteome composed of minimal endogenous modules (MEMOs), functional uniCOREs and regulatory complex-complex interaction networks (CCIs). This resource will effectively fill a void in linking correlative genomic studies with an understanding of transcriptional regulatory protein functions within the proteome for formulation and testing of new hypotheses.

The authors note that, due to a printer's error, on page 5054, right column, second paragraph, eighth line, "Within this clade, we estimated the mean age of the split between the ABC bears and the polar bears to be 152 ky, and the mean age for all polar bears as 134 ky, near the end of the Eemian interglacial period and completely in line with the stratigraphically determined age of the Poolepynten subfossil (11)," should instead appear as "Within this clade, we estimated the mean age of the split between the ABC bears and the polar bears to be 152 ky, and the mean age for all polar bears as 134 ky, near the beginning of the Eemian interglacial period and completely in line with the stratigraphically determined age of the Poolepynten subfossil (11)." This error does not affect the conclusions of the article. This error has been corrected online and in print.www.pnas.org/cgi

The nuclear receptor and bona fide oncogene, steroid receptor coactivator-3 (SRC-3, AIB1), acts as a master transcriptional regulator of breast cancer by transducing growth signals via the estrogen receptor alpha (ER). In this resource paper, we present the genome-wide localization analysis of SRC-3 chromatin affinity sites in MCF-7 human breast cancer chromatin and compare the cis binding sites to global cartographies for ER and FoxA1. By correlating their gene proximal binding sites to integrated gene expression signatures, and in combination with gene ontology analyses, we provide a functional classification of estradiol-induced gene regulation that further highlights an intricate transcriptional control of interdependent cellular pathways by SRC-3. Furthermore, by presenting proteomics analyses of in vivo SRC-3- and ER-associated proteins, we give strong evidence to support the idea that the interpretative power of SRC-3 in estrogen signaling is mediated through the formation of distinct, cell state-dependent protein complexes. Altogether, we present the first approach in complementary comparative analyses that converges results obtained by three discovery-driven methods (cistromics, transcriptomics, and proteomics) into testable hypotheses, thus providing a valuable resource for follow-up studies that further our understanding of estrogen signaling in human diseases in general and breast cancer in particular.

Transcription of eukaryotic cell is a multistep process tightly controlled by concerted action of macromolecules. Nuclear receptors are ligand-activated sequence-specific transcription factors that bind DNA and activate (or repress) transcription of specific sets of nuclear target genes. Successful activation of transcription by nuclear receptors and most other transcription factors requires “coregulators” of transcription. Coregulators make up a diverse family of proteins that physically interact with and modulate the activity of transcription factors and other components of the gene expression machinery via multiple biochemical mechanisms. The coregulators include coactivators that accomplish reactions required for activation of transcription and corepressors that suppress transcription. This review summarizes our current knowledge of nuclear receptor coactivators with an emphasis on their biochemical mechanisms of action and means of regulation.

All cells that constitute mature tissues in an eukaryotic organism undergo a multistep process of cell differentiation. At the terminal stage of this process, cells either cease to proliferate forever or rest for a very long period of time. During terminal differentiation, most of the genes that are required for cell 'housekeeping' functions, such as proto-oncogenes and other cell-cycle and cell proliferation genes, become stably repressed. At the same time, nuclear chromatin undergoes dramatic morphological and structural changes at the higher-order levels of chromatin organization. These changes involve both constitutively inactive chromosomal regions (constitutive heterochromatin) and the formerly active genes that become silenced and structurally modified to form facultative heterochromatin. Here we approach terminal cell differentiation as a unique system that allows us to combine biochemical, ultrastructural and molecular genetic techniques to study the relationship between the hierarchy of chromatin higher-order structures in the nucleus and its function(s) in dynamic packing of genetic material in a form that remains amenable to regulation of gene activity and other DNA-dependent cellular processes.