Polycomb group-dependent Cyclin A repression in Drosophila

Abstract

Polycomb group (PcG) and trithorax group (trxG) proteins are well known for their role in the maintenance of silent and active expression states of homeotic genes. However, PcG proteins may also be required for the control of cellular proliferation in vertebrates. In Drosophila, PcG factors act by associating with specific DNA regions termed PcG response elements (PREs). Here, we have investigated whether Drosophila cell cycle genes are directly regulated by PcG proteins through PREs. We have isolated a PRE that regulates Cyclin A (CycA) expression. This sequence is bound by the Polycomb (PC) and Polyhomeotic (PH) proteins of the PcG, and also by GAGA factor (GAF), a trxG protein that is usually found associated with PREs. This sequence In Drosophila, PcG-mediated repression occurs through cis-regulatory DNA sequences termed PREs (PcG response elements) (Zink et al. 1991;Simon et al. 1993). PREs share several tractable molecular and genetic properties: (1) PcG proteins bind directly to PREs (Zink and Paro 1995; Strutt and Paro 1997); (2) in vivo, PREs induce repression of the adjacent white reporter gene, producing a variegated phenotype (Fauvarque and Dura 1993); (3) this variegated phenotype is dependent on PcG and trxG proteins; and (4) PREs induce pairingsensitive repression (PSR) (for review, see Kassis 2002).Epigenetic regulation of gene expression is emerging as a key mechanism in the control of cellular proliferation. In vertebrates, PRC1 and PRC2/3 components have been implicated in the regulation of proliferation, acting as either potent activators or repressors of the cell cycle. Progression through the cell cycle depends primarily on the activity of the cyclin-dependent kinases (Cdks). Cdks, upon association with their respective cyclin partners, mediate the transitions between the different cell cycle phases. Although with increased complexity, cell Cold Spring Harbor Laboratory Press on May 12, 2018 -Published by genesdev.cshlp.org Downloaded from

Polycomb/Trithorax response elements and epigenetic memory of cell identity

“…We predicted several targets with roles in proliferation, and confirmed PRE/TRE status for one of them (proliferation disrupter) in a transgenic assay (Ringrose et al, 2003). In addition, a recent study of Drosophila S2 cells showed that the cyclin A gene is a PcG target (Martinez et al, 2006), a target which the genome-wide Sg4 cell study did not detect (Schwartz et al, 2006), again strongly suggesting that cell cycle regulation by PcG is cell-type-specific. Indeed, Martinez et al (Martinez et al, 2006) reported tissue-specific effects of PcG on Cyclin A in Drosophila embryos and larvae.…”

“…In addition, a recent study of Drosophila S2 cells showed that the cyclin A gene is a PcG target (Martinez et al, 2006), a target which the genome-wide Sg4 cell study did not detect (Schwartz et al, 2006), again strongly suggesting that cell cycle regulation by PcG is cell-type-specific. Indeed, Martinez et al (Martinez et al, 2006) reported tissue-specific effects of PcG on Cyclin A in Drosophila embryos and larvae. Another recent study has shown that when Delta is overexpressed in the eye, aberrant overexpression of PcG proteins silences the Rbf gene (a homolog of the mammalian retinoblastoma gene), causing severe malignant tumours (FerresMarco et al, 2006).…”

Biphasic MLL takes helm at cell cycle control: Implications in human mixed lineage leukemia

“…For example, they target similar cell cycle genes such as CyclinA and p16. 44,102,103 Furthermore, deregulation of factors belonging to either groups affects hematopoiesis and contributes to various oncogenic processes. 34,35,104,105 Bmi-1, a Pc-G protein, is well recognized for its ability to accelerate Myc-induced lymphoma in mice.…”

Drosophila Polycomb complexes restrict neuroblast competence to generate motoneurons

“…For example, levels of H3K27me3 at the Neurog1 locus increase with each neural progenitor division, providing a potential mechanism for timing the loss of competence to make neurons (Hirabayashi et al, 2009). In Drosophila, PRCs were first identified as regulators of Hox gene expression but have since been shown to control multiple processes, including cell cycle regulation (O'Dor et al, 2006;Martinez et al, 2006), differentiation of germline progenitors (Chen et al, 2005;Narbonne et al, 2004), dendrite remodeling (Parrish et al, 2007) and the diversity of neuronal projection patterns (Wang et al, 2006). Genome-wide mapping of PRC targets in Drosophila suggests that PRCs regulate a wide range of developmental programs (Schwartz et al, 2006;Oktaba et al, 2008;Schuettengruber et al, 2009), including potentially regulating cell fate specification during neurogenesis.…”