Poster Presentation 41st Lorne Genome Conference 2020

Investigation of how the epigenetic regulator Smchd1 regulates Hox gene expression (#110)

Natalia Benetti 1 , Natasha Jansz 1 , Tamara Beck 1 , Kelsey Breslin 1 , Megan Iminitoff 1 , Siew Fen Lisa Wong 2 , Edwina McGlinn 2 , Marnie Blewitt 1
  1. Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. EMBL Australia, Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia

Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is a non-canonical SMC protein that plays a key role in X chromosome inactivation and the epigenetic silencing of several clustered gene families [1-6]. One such example of a clustered gene family that is silenced by Smchd1 is the Hox genes [5, 6]. Jansz et al., found that zygotic Smchd1-null embryos displayed a precocious activation of the Hox genes responsible for posterior vertebral patterning and consequential posterior-shift homeotic transformations in their skeletons, compared to Smchd1 wildtype embryos, indicating that Smchd1 plays an important role in Hox gene silencing [6]. Jansz et al., also reported that the targeting of Smchd1 to the inactive X chromosome is dependent on the H2AK119 ubiquitination activity of Ring1A and Ring1B (components of PRC1) [7]. We have also found that maternal deletion of Smchd1leads to posterior shift homeotic transformations in the skeletal patterning of E17.5 mouse embryos, indicating that maternal Smchd1 may play an important role in establishing chromatin architecture at and/or around the Hox genes that is conducive to correct Hox expression and skeletal patterning later in development. Our experimental plans to further investigate when Smchd1 is silencing the Hox genes involve analysing differential Hox gene expression without Smchd1 at other time points (E8.5 and E10.5 in addition to E9.5), as well as during embryonic stem (ES) cell differentiation experiments in both zygotic and maternally deleted ES cells. We also plan to carry out Hi-C and ChIP experiments to examine differences in chromatin architecture and histone marks with and without zygotic and maternal Smchd1, and to see whether Smchd1’s targeting to the Hox genes is also dependent on the ubiquitination capacity of PRC1, as it is for the maintenance of X chromosome inactivation.

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  3. Mould, A.W., et al., Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenetics & Chromatin, 2013. 6(1): p. 19.
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  5. Chen, K., et al., Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. Proc Natl Acad Sci U S A, 2015. 112(27): p. E3535-44.
  6. Jansz, N., et al., Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters. Nat Struct Mol Biol, 2018. 25(9): p. 766-777.
  7. Jansz, N., et al., Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway. Cell Rep, 2018. 25(7): p. 1912-1923.e9.