Flowering at the right time is crucial to ensure successful plant reproduction and seed yield and is dependent on both environmental and endogenous parameters. Among the different pathways that impinge on flowering, the autonomous pathway promotes floral transition independently of day length through the repression of the central flowering repressor FLOWERING LOCUS C (FLC). FLC blocks floral transition by repressing flowering time integrators such as FLOWERING LOCUS T (FT). MSI4/FVE is a key regulator of the autonomous pathway that reduces FLC expression. Here we report that the MSI4 protein is a DDB1 and CUL4-associated factor that represses FLC expression through its association with a CLF-Polycomb Repressive Complex 2 (PRC2) in Arabidopsis. Thus, the lack of MSI4 or decreased CUL4 activity reduces H3K27 trimethylation on FLC, but also on its downstream target FT, resulting in increased expression of both genes. Moreover, CUL4 interacts with FLC chromatin in an MSI4-dependant manner, and the interaction between MSI4 and CUL4-DDB1 is necessary for the epigenetic repression of FLC. Overall our work provides evidence for a unique functional interaction between the cullin-RING ubiquitin ligase (CUL4-DDB1 MSI4 ) and a CLF-PRC2 complex in the regulation of flowering timing in Arabidopsis.I n the model plant Arabidopsis thaliana, floral transition is regulated by changes in day length and exposure of plants to long periods of low temperature by two well-defined genetic pathways, called photoperiod and vernalization, respectively (reviewed in refs. 1-3). In addition to environmentally controlled pathways, the gibberellic acid-dependent and the autonomous pathways are controlled by internal cues, ensuring flowering independently of external signals. However, input signals that might control the activities of these pathways are currently unknown. These different pathways converge to regulate several target genes at the transcriptional level, resulting in a complex network of flowering-time regulation. Among target genes, FLOWERING LOCUS C (FLC) encodes a MADS-box transcription factor, which quantitatively blocks the floral transition by repressing the expression of the floral integrator genes SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1/AGAMOUS-LIKE 20 (SOC1/AGL20) and FLOWERING LOCUS T (FT). FLC transcriptional regulation is at the convergence of the vernalization pathway that represses FLC after exposure to low temperatures and the autonomous pathway, which constitutively represses FLC (2, 3). In turn, FLC repression results in floral integrator (i.e., FT and SOC1/AGL20) activation, leading to the induction of expression of floral-primordium-identity genes such as APETALA 1 (AP1) and LEAFY (LFY) and floralorgan-identity genes such as AGAMOUS (AG) and AP3, promoting the transition from a vegetative to an inflorescence meristem (1-3).Mutants in the autonomous pathway flower very late when grown under either long-day (LD) or short-day (SD) photoperiods (4). Cloning of the autonomous pathway gene FVE (5, 6) revealed a WD40 ...