Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression

Sanidas, Ioannis; Lee, Hanjun; Rumde, Purva; Boulay, Gaylor; Morris, Robert T.; Golczer, Gabriel; Stanzione, Marcello; Hajizadeh, Soroush; Zhong, Jun; Ryan, Meagan B.; Corcoran, Ryan B.; Drapkin, Benjamin J.; Rivera, Miguel N.; Dyson, Nicholas J.; Lawrence, Michael S.

doi:10.1016/j.molcel.2022.07.014

Cited by 15 publications

(44 citation statements)

References 81 publications

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“…Our in silico evo‐devo approach showed that RBR links with the cell cycle, chromatin and DNA repair/damage regulation pathways through peptide–protein interactions with LxCxE‐containing proteins are highly conserved across the plant kingdom (Figure 4). Functional studies on metazoan models also connect pRB‐LxCxE interactions to DDR (Bourgo et al., 2011) and chromatin regulation pathways (Sanidas et al., 2022), which suggests that pRB and RBR protein interaction networks are very similar between metazoans and green plants, and interaction with these types of regulators could be considered ‘core LxCxE functions’ of pRBs (Figure 4). In contrast, potential interactions with LxCxE‐containing TFs likely diversified throughout land plant evolution as RBR was recruited to different cell‐type‐specific regulatory programs, while some RBR‐LxCxE‐TFs interactions are putatively highly conserved (SCR, FAMA, TCX5, confirmed in Arabidopsis ).…”

Section: Resultsmentioning

confidence: 98%

“…(Bartlett, 2019). Pocket proteins such as pRB and RBR lack DNA‐binding domains and as such are not considered ‘classic’ TFs; however, they are bona fide TRs for their capacity to act synergistically or antagonistically with TFs to regulate gene expression output (Cruz‐Ramírez et al., 2012; Goupille et al., 2017; Gutzat et al., 2011; Johnston et al., 2008; Lang et al., 2021; Matos et al., 2014; Sanidas et al., 2022; Zamora‐Zaragoza, Klap, Heidstra, et al., 2021), thus we speculate that if the pocket and RbN regions of RBR proteins interact and function in a similar way as metazoan pRB, therefore, the loss and/or modification of these regions in the aforementioned streptophyte algae RBR orthologs could impinge on RBR structural regulation and possibly function; however, more research is needed to characterize the RbN region in RBR proteins to determine how these modifications could influence RBR function.…”

Section: Resultsmentioning

confidence: 99%

“…Because RBR functions as a scaffold to tether different proteins together, it is probable that RBR forms part of PHD‐domain associated complexes and such interactions may be a conserved RBR feature in the Chloroplastida (Figures 3 and 4). Experimental evidence shows that human pRB binds different types of chromatin marks at different genomic regions such as promoters via E2F (high in H3K4Me3) and cell‐type specific enhancers (high in H3K4me1 and H3K27ac1) in a highly plastic manner as the distribution of chromatin‐bound pRB changes dynamically throughout the cell cycle between promoters and enhancers, with pRB preferentially bound to promoters when the cell cycle is arrested and pRB bound to enhancers when cells enter S‐phase (Sanidas et al., 2022). Our results suggest that putative interactions with a variety of families of chromatin‐binding proteins (SWI/SNF2 remodelers, SET HMTs, GNAT HATs and PHD proteins; Figure 3, right) are a highly conserved type of interaction in Chloroplastida RBR and, as pRBs lack DNA‐binding domains, it is very probable that pRB/RBR chromatin interplay occurs at least partly through dynamic interaction with LxCxE‐containing chromatin‐binding proteins, indicating that Retinoblastoma chromatin‐binding function is conserved between metazoans and plants (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

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Predicted landscape of RETINOBLASTOMA‐RELATED LxCxE‐mediated interactions across the Chloroplastida

León‐Ruiz¹,

Ramírez²

2022

The Plant Journal

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SUMMARY The colonization of land by a single streptophyte algae lineage some 450 million years ago has been linked to multiple key innovations such as three‐dimensional growth, alternation of generations, the presence of stomata, as well as innovations inherent to the birth of major plant lineages, such as the origins of vascular tissues, roots, seeds and flowers. Multicellularity, which evolved multiple times in the Chloroplastida coupled with precise spatiotemporal control of proliferation and differentiation were instrumental for the evolution of these traits. RETINOBLASTOMA‐RELATED (RBR), the plant homolog of the metazoan Retinoblastoma protein (pRB), is a highly conserved and multifunctional core cell cycle regulator that has been implicated in the evolution of multicellularity in the green lineage as well as in plant multicellularity‐related processes such as proliferation, differentiation, stem cell regulation and asymmetric cell division. RBR fulfills these roles through context‐specific protein–protein interactions with proteins containing the Leu‐x‐Cys‐x‐Glu (LxCxE) short‐linear motif (SLiM); however, how RBR‐LxCxE interactions have changed throughout major innovations in the Viridiplantae kingdom is a question that remains unexplored. Here, we employ an in silico evo‐devo approach to predict and analyze potential RBR‐LxCxE interactions in different representative species of key Chloroplastida lineages, providing a valuable resource for deciphering RBR‐LxCxE multiple functions. Furthermore, our analyses suggest that RBR‐LxCxE interactions are an important component of RBR functions and that interactions with chromatin modifiers/remodelers, DNA replication and repair machinery are highly conserved throughout the Viridiplantae, while LxCxE interactions with transcriptional regulators likely diversified throughout the water‐to‐land transition.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Predicted landscape of RETINOBLASTOMA‐RELATED LxCxE‐mediated interactions across the Chloroplastida

León‐Ruiz¹,

Ramírez²

2022

The Plant Journal

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“…Indeed, other DNA sequences, such as cell cycle homology region sites, were shown to help in tethering the E2F complex to DNA as a part of the MuvB complex (Müller et al , 2014). Additionally, it has been suggested that other DNA binding factors may facilitate E2F binding (Rabinovich et al , 2008; Sanidas et al , 2022). Overall, our results suggest that, unlike in vitro assays with recombinant proteins, mutation of E2F sites does not always fully prevent the recruitment of E2F in vivo .…”

Section: Discussionmentioning

confidence: 99%

The binding sites of E2F transcription factor inDrosophilametabolic genes are functionally distinct

Zappia

Kwon

Westacott

et al. 2022

Preprint

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The canonical role of the transcription factor E2F is to control the expression of cell cycle genes by binding to the E2F sites in their promoters. However, the list of putative E2F target genes is extensive and includes many metabolic genes, yet the significance of E2F in controlling expression of these genes remains largely unknown. Here, we used the CRISPR/Cas9 technology to introduce point mutations in the E2F sites upstream of five endogenous metabolic genes in Drosophila. We found that the impact of these mutations on both the recruitment of E2F and the expression of the target genes varied, with the glycolytic gene, Phosphoglycerate kinase (Pgk), being mostly affected. The loss of E2F regulation on Pgk gene led to a decrease in glycolytic flux, TCA cycle intermediates levels, ATP content and an abnormal mitochondrial morphology. Remarkably, chromatin accessibility was significantly reduced at multiple genomic regions. Collectively, our results illustrate how the pleiotropic effects on metabolism, gene expression and development in the PgkΔE2Fanimals underscore the importance of E2F regulation on a single E2F target, Pgk.

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“…There are other non-canonical activities of pRB that could play a role in MmuPV1 E7′s interaction with pRB including pRB’s interactions with ABL1 nonreceptor tyrosine kinase and F-box protein SKP2 [ 191 , 192 ]. A new study that examined how pRB binding sites are distributed across the genome and what transcription factors interact with pRB outside E2F proteins showed that pRB binds to AP1 and CTCF sites [ 193 ]. It will be interesting to determine whether MmuPV1 E7 affects pRB binding to these sites.…”

Section: How Do Mmupv1 E6 and E7 Relate To The Hpv E6 And E7 Proteins?mentioning

confidence: 99%

Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease

Romero-Masters

Lambert

Münger

2022

Viruses

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Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes.

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Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression

Cited by 15 publications

References 81 publications

Predicted landscape of RETINOBLASTOMA‐RELATED LxCxE‐mediated interactions across the Chloroplastida

Predicted landscape of RETINOBLASTOMA‐RELATED LxCxE‐mediated interactions across the Chloroplastida

The binding sites of E2F transcription factor inDrosophilametabolic genes are functionally distinct

Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease

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