Dynamic combinatorial networks in nuclear receptor-mediated transcription

The nuclear hormone receptor ( NR)(2) superfamily describes a diverse array of transcription activators working in a ligand- dependent manner and exerting action by regulating the expression of specific subsets of genes ( 1, 2). The receptors for steroid hormones, which include the estrogen ( ER), androgen ( AR), progesterone ( PR), and glucocorticoid ( GR) receptors, are held in the cytoplasm, in association with chaperone complexes. Ligand binding acts as an on- switch, inducing their release from the chaperone molecules, their dimerization, their entrance into the nucleus, and their binding to hormone response elements ( HREs) within the regulatory regions of target genes. In contrast, the receptors for non- steroidal hormones such as the vitamin D ( VDR), retinoic acid ( RARs), and peroxisome proliferator- activated ( PPAR) receptors are found primarily in the nucleus and bound at HREs as heterodimers with the retinoid X receptor ( RXR). They are associated with histone deacetylase- containing complexes tethered through corepressors ( N- CoR and SMRT), resulting in chromatin compaction and gene silencing. Upon ligand binding, the corepressor- binding interface of NRs is destabilized, leading to the dissociation of corepressors ( 3). The basic mechanism for switching on gene transcription by liganded NRs ( either steroid or non- steroid) relies on a complex and ever growing network of interactions with coregulatory proteins. For most NRs, this network is directed by a specific domain, the activation function 2 ( AF- 2) domain, located in the C- terminal ligand- binding domain ( LBD) ( Fig. 1A). The LBD is composed of 12 alpha helices organized as an antiparallel sandwich ( Fig. 1B). Upon ligand binding, the AF- 2 domain undergoes major structural rearrangements ( 4, 5), creating a new binding surface for coactivators ( Fig. 1B). The AF- 2 domain cooperates with a second activation domain residing in the N terminus, the AF- 1 domain ( 4), to recruit multiple complexes to alter the chromatin structure surrounding the promoter of target genes ( 6 - 8). In the end these events pave the way for the recruitment of the transcription machinery, including RNA polymerase II ( RNA PolII) and the general transcription factors ( GTFs) ( 9). A concept that has developed over the last several years is that NRs and their coregulators are subjected to rapid modifications ( phosphorylation, ubiquitination, acetylation, methylation) and proteasomal degradation. Therefore it emerged that they exert transcriptional control in a combinatorial, coordinated, coordinated, and sequential manner. These findings challenged the conventional view of stable, NR- based, template- bound complexes and suggested a dynamic and multistep model involving rapid and carefully orchestrated series of exchanges between NRs, coregulators, and the promoter. In this review, we will focus on the dynamics of the interactions between NRs and their coregulators and on their fine tuning by a variety of post- translational modifications or degradation processes that occur in response to the ligand or to other cellular signalings, so that, in the end, the correct proteins are present with the right activity, at the right place, and at the right time.