Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters (Published: 20 August 2018)

In this year’s September edition of Nature Structural and Molecular Biology, Associate Professor Marnie Blewitt’s laboratory revealed that the noncanonical SMC protein Smchd1 is a novel regulator of long-range chromatin interactions in mice. The study, conducted primarily at the Walter and Eliza Hall Institute of Medical Research in Melbourne, tested the role of Smchd1 in maintaining chromosome structure using in situ Hi-C in Smchd1 depleted female mice. In doing so the authors discovered a role for Smchd1 in regulating Hox clusters in particular -

thus adding to the canon of proteins known to epigenetically regulate Hox gene silencing during development. The report focused on the effect of losing Smchd1-dependent chromatin interaction in the inactive X (Xi) chromosome. This showed an increase in X-linked chromatin interaction in the absence of Smchd1, without the expected increase in reactivation of genes from the Xi. Instead, the report reveals, “spreading of trimethylated histone H3K27 domain into regions not normally decorated by this mark” on Smchd1 depleted Xi. The authors conclude that Smchd1 is able to insulate chromatin to limit access to other chromatin-modifying proteins and thereby regulate long-range chromatin interactions, thus adding to our understanding of how chromatin architecture is regulated. For the Full-Text Article: https://www.nature.com/articles/s41594-018-0111-z

Epigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy (Published: 17 August 2018) From Melbourne’s Murdoch Children’s Research Institute, Professor Richard Saffery and colleagues have published an investigation on naïve CD4+ T cell activation in a cohort of infants with egg allergy. The study design involved activating T cells from non-atopic (control) and atopic individuals under non-differentiating conditions, and then profiling DNA methylation, gene expression and cell proliferation in these cells. The authors gained insight into naïve T cell responsiveness to activation. Comparison between the two groups showed that infants with food allergies have gene dysregulation in their T cell activation pathways leading to

poor lymphoproliferative responses. The study reveals that the suboptimal T cell responses are underpinned by “reduced expression of cell cycle–related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic (RPTOR, PIK3D, MAPK1, FOXO1) and inflammatory genes (ILIR,

ILI8RAP, CD82)”. The pathway modifications by gene-environment interactions seen in food allergy are thereby connected to epigenetic dysregulation in the early stages of signal transduction from the T cell receptor complex. For the Full-Text Article: https://www.nature.com/articles/s41467-018-05608-4

The state of long non-coding RNA biology (Published: 10 August 2018) This June, the journal non-coding RNA published a review by Professor John Mattick, who has recently moved from the Garvan Institute of Medical Research in Sydney to Genomics England in London. In the review titled ‘The State of Long Non-Coding RNA Biology,’ Professor Mattick states that long non-protein-coding RNAs (lncRNAs) “are still to be widely accepted as major players in gene regulation.” This, he asserts, is “despite well characterized examples, their scaling with developmental complexity, and many demonstrations of their association with cellular process, development and diseases.” The review shines the spotlight on lncRNAs, starting with the history of their discovery and continuing to go into detail of the structure-function relationships of IncRNAs, which the review claims is “the most pressing challenge” to resolving the IncRNAs functional repertoire. The review ends by making the statement that RNA is “not (simply) . . . a transient intermediate between gene and protein, but rather the central computational engine of cell biology, differentiation and development, brain function and perhaps even evolution itself” and predicting that “many textbooks may have to be rewritten once the full dimensions of regulatory RNA biology are revealed.” For the Full-Text Article: https://doi.org/10.1111/cea.13031

For the Full-Text Article: https://www.nature.com/articles/s41467-017-01393-8

RNA-dependent epigenetic silencing directs transcriptional downregulation caused by intronic repeat expansions (Published: 26 July 2018)

From Melbourne’s Monash University, this study delves into transcriptional downregulation caused by intronic triple expansions. Expansion of trinucleotide repeats in intronic regions, as seen in diseases such as Friedreich’s ataxia and fragile X, can be expansive, with the possibility of up to 2,000 repeats. How these repeats lead to reduction in certain protein expression in these diseases was the interrogated question. Led by Associate Professor Sureshkumar Balasubramanian and published in Cell in August this year, the report revealed that: “triple repeat expansions can lead to local siRNA biogenesis, which in turn down regulates transcription”. The study goes on to show that this deregulation is mediated by RNA-dependent DNA methylation (RdDM) epigenetic

modifications. Using an IIL1 repeat expansion in Arabidposis Thaliana, the authors unravel this molecular mechanism for the transcriptional downregulation in Arabidopsis. The report points to the need to assess RNA-dependent transcriptional gene silencing pathways to further understand the epigenetic attenuation of protein expression, particularly for disease conditions such as Friedreich’s ataxia. https://www.nature.com/articles/ijo2017228

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