ESTROGEN INDUCES DYNAMIC ER AND RING1B RECRUITMENT TO CONTROL GENE AND ENHANCER ACTIVITIES IN LUMINAL BREAST CANCER
Science Advances, 2020
RING1B, a core Polycomb Repressive Complex 1 subunit, is a histone H2A ubiquitin ligase essential for early development. RING1B is overexpressed in patients with luminal breast cancer and is recruited to actively transcribed genes and enhancers co-occupied by the estrogen receptor alpha (ERa). Whether ERa-induced transcriptional programs are mediated by RING1B is not understood. Here, we show that prolonged estrogen (E2) administration induces transcriptional output and chromatin landscape fluctuations. RING1B loss impairs full E2-mediated gene expression as well as chromatin accessibility for key breast cancer transcription factors. These gene-specific effects were mediated, in part, by RING1B enzymatic activity and nucleosome binding functions. We also found that RING1B is recruited in a cyclic manner to ERa, FOXA1 and GRHL2 co-bound sites during E2 administration and regulates E2-induced enhancers and ERa recruitment. Finally, ChIP-exo assays unveiled multiple binding events of these four factors at single-nucleotide resolution, including RING1B occupancy approximately 10bp around ERa bound sites. We propose RING1B as a key regulator of the dynamic and liganded-ERa transcriptional regulatory circuit in luminal breast cancer.
POLYCOMB COMPLEXES ASSOCIATE WITH ENHANCERS AND PROMOTE ONCOGENIC TRANSCRIPTIONAL PROGRAMS IN CANCER THROUGH MULTIPLE MECHANISMS
Nature Communications, 2018
Polycomb repressive complex 1 (PRC1) plays essential roles in cell fate decisions and development. However, its role in cancer is less well understood. Here, we show that RNF2, encoding RING1B, and canonical PRC1 (cPRC1) genes are overexpressed in breast cancer. We find that cPRC1 complexes functionally associate with ERα and its pioneer factor FOXA1 in ER+ breast cancer cells, and with BRD4 in triple-negative breast cancer cells (TNBC). While cPRC1 still exerts its repressive function, it is also recruited to oncogenic active enhancers. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of oncogenes but also by regulating chromatin accessibility. Functionally, RING1B plays a divergent role in ER+ and TNBC metastasis. Finally, we show that concomitant recruitment of RING1B to active enhancers occurs across multiple cancers, highlighting an under-explored function of cPRC1 in regulating oncogenic transcriptional programs in cancer.
POLYCOMB REGULATES MESODERM CELL FATE-SPECIFICATION IN EMBRYONIC STEM CELLS THROUGH ACTIVATION AND REPRESSION MECHANISMS.
Cell Stem Cell, 2025
Polycomb complexes (PRC1 and PRC2) are essential regulators of epigenetic gene silencing in embryonic and adult stem cells. Emerging evidence suggests that the core subunit composition regulates distinct biological processes, yet little is known about the mechanistic underpinnings of how differently composed Polycomb complexes instruct and maintain cell fate. Here we find that Mel18, also known as Pcgf2 and one of six Pcgf paralogs, uniquely regulates PRC1 to specify mesoderm cell fate in embryonic stem cells. Mechanistically, Mel18 functions as a classical Polycomb protein during early cardiac mesoderm differentiation by repressing pluripotency, lineage specification, late cardiac differentiation, and negative regulators of the BMP pathway. However, Mel18 also positively regulates expression of key mesoderm transcription factors, revealing an unexpected function of Mel18 in gene activation during cardiac differentiation. Taken together, our findings reveal that Mel18 is required to specify PRC1 function in both a context- and stage-specific manner.
NONOVERLAPPING FUNCTIONS OF THE POLYCOMB GROUP CBX FAMILY OF PROTEINS IN EMBRYONIC STEM CELLS
Cell Stem Cell, 2012
Polycomb group proteins are essential regulators of cell fate decisions during embryogenesis. In mammals, at least five different Cbx proteins (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8) are known to associate with the core Polycomb repressive complex 1 (PRC1). Here we show that pluripotency and differentiation of mouse embryonic stem cells (ESCs) is regulated by different Cbx-associated PRC1 complexes with unique functions. Maintenance of pluripotency primarily depends on Cbx7, while lineage commitment is orchestrated by Cbx2 and Cbx4. At the molecular level, we have uncovered a Polycomb autoregulatory loop in which Cbx7 represses the expression of prodifferentiation Cbx proteins, thereby maintaining the pluripotent state. We additionally show that the occupancy of Cbx7 on promoters is completely dependent on PRC2 activity but only partially dependent on a functional PRC1 complex. Thus, Cbx proteins confer distinct target selectivity to the PRC1 complex, achieving a balance between the self-renewal and the differentiation of ESCs.
RYBP AND CBX7 DEFINE SPECIFIC BIOLOGICAL FUNCTIONS OF POLYCOMB COMPLEXES IN MOUSE EMBRYONIC STEM CELLS
Cell Reports, 2013
The Polycomb repressive complex 1 (PRC1) is required for decisions of stem cell fate. In mouse embryonic stem cells (ESCs), two major variations of PRC1 complex, defined by the mutually exclusive presence of Cbx7 or RYBP, have been identified. Here, we show that although the genomic localization of the Cbx7- and RYBP-containing PRC1 complexes overlaps in certain genes, it can also be mutually exclusive. At the molecular level, Cbx7 is necessary for recruitment of Ring1B to chromatin, whereas RYBP enhances the PRC1 enzymatic activity. Genes occupied by RYBP show lower levels of Ring1B and H2AK119ub and are consequently more highly transcribed than those bound by Cbx7. At the functional level, we show that genes occupied by RYBP are primarily involved in the regulation of metabolism and cell-cycle progression, whereas those bound by Cbx7 predominantly control early-lineage commitment of ESCs. Altogether, our results indicate that different PRC1 subtypes establish a complex pattern of gene regulation that regulates common and nonoverlapping aspects of ESC pluripotency and differentiation.