Enhancer-promoter dynamics are critical for the spatiotemporal control of gene expression, but it remains unclear how these dynamics are controlled by chromatin regulators, such as the nucleosome remodelling and deacetylase (NuRD) complex. Here, we use Hi-C experiments to show that the intact NuRD complex increases CTCF/Cohesin binding and the probability of the interaction of intermediate-range (~1Mb) genomic sequences.To understand how NuRD alters 3D genome structure in this way, we developed an approach to segment and extract key biophysical parameters from trajectories of the NuRD complex determined using live-cell 3D singlemolecule imaging. Unexpectedly, this revealed that the intact NuRD complex decompacts chromatin structure and makes NuRD-bound sequences move faster, thus increasing the overall volume of the nucleus that these sequences explore. Interestingly, we also uncovered a rare fast-diffusing state of chromatin that exhibits directed motion. The intact NuRD complex reduces the amount of time that enhancers/promoters remain in this fastdiffusing state, which we propose would otherwise re-organise enhancer-promoter proximity. Thus, we uncover an intimate connection between a chromatin remodeller and the spatial dynamics of the local region of the genome to which it binds.3D genome organisation is thought to be critical for the spatiotemporal control of gene expression. However, little is known about the multi-scale chromatin dynamics of cis-regulatory elements or how they relate to genome organisation. To probe these dynamics at the single-cell level, one of two complementary methods are typically used: either live-cell imaging 1-4 or single nucleus versions of chromosome conformation capture experiments (such as Hi-C), which reveal the proximity of DNA sequences in different individual fixed cells [5][6][7][8][9][10][11][12][13][14][15][16] . For example, live-cell tracking of enhancers and promoters has revealed fast diffusion (or 'stirring') during transcription 4 , but the mechanisms underlying these changes in enhancer dynamics or how they relate to Hi-C measurements of enhancer-promoter proximity remain unclear.The nucleosome remodelling and deacetylase (NuRD) complex is a highly conserved 1 MDa multisubunit protein complex that we have previously shown clusters in 3D space in the nucleus with active enhancers and promoters 16 . It combines two key enzymatic activities -nucleosome remodelling via its helicasecontaining ATPase (predominantly CHD4 in ES cells) and lysine deacetylation via its HDAC1/2 subunits [16][17][18][19][20][21][22] .These activities are thought to be present in two sub-complexes (Figure 1a). HDAC1/2 associates, along with the histone chaperones RBBP4/7, with the core scaffold proteins MTA1/2/3 (metastasis tumour antigens) to form a stable sub-complex with deacetylase activity 23 . The nucleosome remodeller CHD4 interacts with chromatin by itself and may also form a second sub-complex with GATAD2A/B and DOC1 (CDK2AP1) 23-25 .The methyl-CpG DNA binding domain proteins MBD2/3 ...
In mammals, both sterile wounding and infection induce inflammation and activate the innate immune system, and the combination of both challenges may lead to severe health defects, revealing the importance of the balance between the intensity and resolution of the inflammatory response for the organism’s fitness. Underlying mechanisms remain however elusive. Using Drosophila, we show that, upon infection with the entomopathogenic bacterium Pseudomonas entomophila (Pe), a sterile wounding induces a reduced resistance and increased host mortality. To identify the molecular mechanisms underlying the susceptibility of wounded flies to bacterial infection, we analyzed the very first steps of the process by comparing the transcriptome landscape of infected (simple hit flies, SH), wounded and infected (double hit flies, DH) and wounded (control) flies. We observed that overexpressed genes in DH flies compared to SH ones are significantly enriched in genes related to stress, including members of the JNK pathway. We demonstrated that the JNK pathway plays a central role in the DH phenotype by manipulating the Jra/dJun activity. Moreover, the CrebA/Creb3-like transcription factor (TF) and its targets were up-regulated in SH flies and we show that CrebA is required for mounting an appropriate immune response. Drosophila thus appears as a relevant model to investigate interactions between trauma and infection and allows to unravel key pathways involved.
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