Our work published in Cell last year ( Ricci MA, Manzo C, García-Parajo M, *Lakadamyali M, and *Cosma MP (2015). Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo. Cell, *co-last authors. Nominated F1000Prime 2015) has been selected to be among the best 8 research in Spain. In collaboration with the group of Melike Lakadamyali using super resolution microscopy we dissected out the nanoscale organisation of the nucleosome assembly in a variety of somatic and stem/ reprogrammed cells. We discovered that nucleosomes are arranged into discrete groups, which we called ‘nucleosome clutches’ (in analogy with egg clutches) and not in a regular hierarchical structure, as it was believed for a long time and is reported in textbooks. Nucleosome median number and clutch compaction correlate closely with cellular state.
Picture by David Airob, La Vanguardia
The Cosma lab discovered that activation of the Wnt/beta-catenin signalling pathway enhances cell-fusion-mediated reprogramming of a variety of somatic cells (Lluis et al., Cell Stem Cell 2008, Stem Cells 2010). Furthermore, the lab proposed that Tcf3 functions as a repressor of the reprogramming potential of somatic cells by largely modulating epigenome modifications during the reprogramming process (Lluis et al., PNAS 2011; Ombrato et al., Cell Cycle 2012). Further key observations showed that fluctuations of the Wnt signalling pathway control the maintenance of mESC pluripotency and are essential for reprogramming (Marucci et al. Cell Reports 2014; Aulicino et al. Stem Cell Reports 2014; Aulicino et al. Stem Cell Reports 2020). The lab also showed that Wnt activity regulates cell cycle in mESCs and safeguards mESCs epigenetic stability (De Jaime-Soguero et al, Plos Genetics 2017; Theka et al. Scientific Reports 2019). Recently In collaboration with Andrea Califano (Columbia University, USA) we used reverse engineering algorithms to identify “Master Regulators” (MRs) of reprogramming and pluripotency. We identified BAZ2B as an MR able to convert human hematopoietic progenitors into hematopoietic stem cells enhancing their long-term clonogenicity and stemness after transplantation (Arumugam et al. Cell Reports, 2020).
Decoding chromatin and DNA structure in cells undergoing reprogramming and differentiation, using super-resolution microscopy.
Using super-resolution fluorescence microscopy (stochastic optical reconstruction microscopy; STORM) in collaboration with Lakadamyali lab (UPENN, USA) we identified a novel model of chromatin fibre organization and decoded the relation between this structure and naïve pluripotency (Ricci et al. Cell 2015). Furthermore, we set up a novel approach to image non-repetitive genomic regions with nanoscale resolution and in living cells (Neguembor et al. NAR 2018). We also visualize how histone tail acetylation impacts DNA compaction at nanoscale level and identified the clutch DNA lying within a specific nanoscale zone from the center of the nucleosome clutch (Otterstrom et al, NAR 2019). Finally, using single molecule tracking (SMT) we showed that nucleosomes are dynamic and their local mobility within chromatin relates to the structural features observed in super-resolution images and mesoscale models (Gomez-Garcia et al. Cell Reports, in press). Using super resolution microscopy, we are interested in studying the 3D genome organization (Cosma & Lakadamyali Nature Methods 2020) and we are currently investigating mechanism of chromatin loop formation.