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The Combined Action of Esrrb and Nr5a2 Is Essential for Naïve Pluripotency

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The Combined Action of Esrrb and Nr5a2 Is Essential for Naïve Pluripotency bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.134999; this version posted June 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency. Nicola Festuccia1,2,*, Nick Owens3, Almira Chervova2, Agnès Dubois2, and Pablo Navarro2 1MRC London Institute of Medical Sciences (LMS), Imperial College London, Du Cane Road, W12 0NN London, UK 2Epigenomics, Proliferation, and the Identity of Cells, Department of Developmental and Stem Cell Biology, Institut Pasteur, CNRS UMR3738, 75015 Paris, France 3Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK *Corresponding author: [email protected] The maintenance of pluripotency in mouse embryonic stem cells both during early differentiation (Festuccia et al., 2018a) (ESCs) is governed by the action of an interconnected network and, conversely, during reprogramming to induced pluripo- of transcription factors. Among them, only Oct4 and Sox2 have tency (Adachi et al., 2018); it orchestrates the recruitment of been shown to be strictly required for the self-renewal of ESCs the transcriptional machinery (Bell et al., 2020; Percharde and pluripotency, particularly in culture conditions where dif- et al., 2012) and other transcription factors (Adachi et al., ferentiation cues are chemically inhibited. Here, we report that 2018) to key regulatory elements of the pluripotency network the conjunct activity of two orphan nuclear receptors, Esrrb (Whyte et al., 2013); it maintains its binding activity dur- and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve ESCs. By occupying a large common set of regulatory el- ing mitosis, directly contributing to the stability of pluripo- ements, these two factors control the binding of Oct4, Sox2 and tency during cell division (Festuccia et al., 2016). Given Nanog to DNA. Consequently, in their absence the pluripotency these characteristics, it is therefore not surprising that the network collapses and the transcriptome is substantially dereg- genetic ablation of Esrrb is profoundly detrimental to ESCs ulated, leading to the differentiation of ESCs. Altogether, this self-renewal in conventional culture conditions (Festuccia et work identifies orphan nuclear receptors, previously thought to al., 2012). In contrast, the loss of Esrrb is tolerated in culture be performing supportive functions, as a new set of core regula- conditions that more stringently enforce the maintenance of tors of naïve pluripotency. the undifferentiated state (Martello et al., 2012) and which involve blocking the differentiation cues imparted by ERK signalling and reinforcing the activation of WNT by GSK3b Introduction inhibition (Ying et al., 2008). How ESCs accommodate the The uncommitted identity of mouse Embryonic Stem (ES) concomitant disruption of the multiple aspects of Esrrb action cells is maintained by the activity of a gene regulatory net- remains unclear, representing a major gap in our knowledge work that strictly depends on the function of Oct4 and Sox2 of the molecular control of ESCs. (Yeo and Ng, 2013). Binding DNA in complex with Sox2 One simple hypothesis to molecularly explain how 2i/LIF (Tapia et al., 2015), Oct4 enables the recruitment of other can bypass the requirements for Esrrb activity is that other transcription factors (TFs) at regulatory regions (King and TFs might be performing a compensatory role. Of note, Esrrb Klose, 2017). In accord, altering the expression of Oct4 or is part of a broad family of TFs, orphan nuclear receptors, that Sox2 results in the differentiation of ESCs. In line with their show high sequence and structural homology, and play over- role in ESCs, Oct4 and Sox2 are essential for epiblast spec- lapping developmental functions (Festuccia et al., 2018b). ification (Avilion et al., 2003; Nichols et al., 1998). Along- Among these, Nr5a2 interacts with Esrrb (van den Berg et side, a number of auxiliary factors stabilise the pluripotency al., 2010) and binds to nearly identical half-palindromic se- network. While their individual depletion often affects the quences through a related DNA binding domain presenting a efficiency of self-renewal (Chambers et al., 2007) and mod- common extension to the conventional zinc-finger of nuclear ulates Oct4 and Sox2 binding at a subset of regulatory ele- receptors (Heng et al., 2010; Solomon et al., 2005). Further, ments (Heurtier et al., 2019), the loss of these TFs does not Nr5a2 is expressed in ESCs, where it contributes to support- result in overt differentiation. For these reasons, it is gen- ing, or instating, pluripotency (Guo and Smith, 2010; Heng erally considered that the pluripotency network is structured et al., 2010). To test whether Nr5a2 mitigates the conse- along two distinct modules: the core network centred on the quences of loss of Esrrb function, we concomitantly ablated master regulators Oct4 and Sox2, and a cohort of supportive both TFs. Here, we report that the loss of both Esrrb and transcription factors. Nr5a2 leads to the complete abrogation of self-renewal and Among all auxiliary TFs, Esrrb is prominent (Festuccia the induction of differentiation even in 2i/LIF. These effects et al., 2018b), controlling multiple aspects of the molecular are mediated by the full collapse of the pluripotency network: wiring of ESC identity: Esrrb is a pivotal mediator of pro- Oct4, Sox2 and Nanog binding is acutely lost at most ESC self-renewing signalling cues, operating downstream of the enhancers and ESC-specific gene expression is shut down. canonical WNT pathway (Martello et al., 2012), and bypass- Our results identify Esrrb and Nr5a2 as a new set of essen- ing the dependence of ESCs on the LIF cytokine (Festuccia tial regulators of pluripotency, whose collective importance et al., 2012); it acts as a major gatekeeper of pluripotency, parallels that of Oct4 and Sox2 in ESCs. N. Festuccia et al. | bioRχiv | June 5, 2020 | 1–14 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.134999; this version posted June 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Fig. 1. Overlapping expression and bind- A C FCS/LIF ing patterns of Esrrb and Nr5a2. (A) Esrrb- DNA Esrrb-mCherry Nr5a2-GFP T2a-GFP (red) and Nr5a2-T2a-GFP (blue) flu- 100 Esrrb DNA Esrrb NR5a2 orescence levels (percentage of mode in each 80 NR5a2 e dataset) determined by flow cytometry in ESC d Neg o 60 cultured in FCS/LIF. In black, background lev- m f o 40 els measured in wild-type E14Tg2a ESCs. (B) % Nr5a2-GFP and Esrrb-mCherry levels in dou- 20 ble knock-in ESCs cultured in FCS/LIF (black) 0 or 2i/LIF (magenta), as determined by imag- 0 200K 400K 600K 800K B GFP 2i/LIF ing flow cytometry (ImageStream). (C) Confo- 300K DNA Esrrb-mCherry Nr5a2-GFP DNA Esrrb NR5a2 cal microscopy images showing Esrrb-mCherry FCS/LIF y and Nr5a2-GFP expression in double knock-in r r 2i/LIF e 200K ESCs cultured in FCS/LIF (top) or 2i/LIF (bot- h C tom). Note double-negative ESCs (white arrow- m - b heads) exist only in FCS/LIF. (D) Profiles of Es- r r 100K s rrb and Nr5a2 binding as determined by ChIP- E seq in proximity of the Sall1 and Foxd3 genes, 0 0 10K 20K 30K 40K 50K highlighting examples of the binding preference Nr5a2-GFP of each TF at common targets (arrowheads). (E) D E Venn diagram showing the intersection between Sall1 Foxd3 NR5a2 regions called as peaks for Esrrb and Nr5a2 34% Esrrb 61% (detected in all replicates, see Methods for de- (9940) (5616) 4% tails). (F) Local enrichment heatmap compar- Nr5a2 Esrrb (724) ing Esrrb (left, red) and Nr5a2 (right, blue) oc- cupancy at regions bound by either of the two f 2 f i i TFs. Esrrb/Nr5a2 peaks were ordered by de- t t a rrb o o s F G H r5 creasing Nr5a2 signal (mean Reads Per Million m Esrrb Nr5a2 E m N 2 > a > - – RPM) and averaged every 20 regions. The full - rrb ) 1.5 r5 s T C M E N paired-end fragments were marked. (G) DNA P 1 R Esrrb ( sequence identified by de-novo motif discovery 2 0.5 5 0mm g ) at all Esrrb/Nr5a2 target regions (top); note the o M 1mm L 0 2.5 7th base can either be a T or a C. Boxplots show- No (RP ing Esrrb and Nr5a2 binding (RPM) at target ) 1.5 0 motif M regions containing tcaaggTca, tcaaggCca, both Log2 P 1 Both R motifs or none, indicating the 7th base of the mo- ( -2.5 2 0.5 T -> Esrrb g tif discriminates Esrrb (T) or Nr5a2 (C) prefer- o Nr5a2 C -> Nr5a2 L 0 5 No motif ential binding. (H) Heatmaps presenting Esrrb ) ) and Nr5a2 occupancy (RPM) at target regions M 3 2.5 M 2 ordered by descending Esrrb/Nr5a2 ratio (left), (RP (RP 1 0 along the occurrence of the Esrrb or Nr5a2 motif 0 Log2 as a function of the number of mismatches (mm; Log2 -1 -2.5 right). Results or negative for the second (Fig 1B, C). Nonetheless, possibly as a consequence of the lower expression levels, Nr5a2 down- Esrrb and Nr5a2 are co-expressed in individual ES cells regulation is overall more frequently observed, as confirmed and bind together at regulatory elements. by single-cell gene expression analysis (Fig 1C, S2B,C).
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