Publications

This month’s highlighted publication in PLOS Genetics, led by Sara Cuvertino, Evgenii Martirosian and Profs Susan Kimber and Siddharth Banka, investigates how KMT2D variants causing Kabuki syndrome type 1 (KS1) affect neuronal development. Using induced pluripotent stem cells (iPSCs) from individuals with KS1 differentiated into neuronal progenitors and cortical neurons, the authors track epigenomic and transcriptomic changes across three stages. They show reduced functional KMT2D transcript and protein in KS1 cells, with global loss of H3K4me1/H3K4me2 and modest reduction of H3K4me3.

Genome-wide profiling reveals thousands of H3K4me1 peaks specifically lost in KS1 iPSCs, neuronal progenitors and cortical neurons, with more sites affected as differentiation progresses and many losses at putative enhancers. In parallel, RNA sequencing identifies hundreds of differentially expressed genes at each stage, including regulators of brain development, yet fewer genes are altered at later stages over time, suggesting partial buffering in more mature neurons.

Integrative analyses link downregulated genes to enhancer regions with H3K4me1 loss and implicate deregulated Polycomb-regulated transcriptional networks as candidate drivers of KS1 neurodevelopmental phenotypes. Overall, this work establishes a disease-relevant human cellular model of KS1 that connects KMT2D haploinsufficiency to widespread enhancer and gene-expression dysregulation and provides a platform for mechanistic studies and future therapeutic screening.

Reference:

Cuvertino S, Martirosian E, Bhosale K, Cheng P, Garner T, Donaldson IJ, Jackson A, Stevens A, Sharrocks AD, Kimber SJ, Banka S. Epigenome and transcriptome changes in KMT2D-related Kabuki syndrome Type 1 iPSCs, neuronal progenitors and cortical neurons. PLoS Genet. 2025 Sep 19;21(9):e1011608. doi: 10.1371/journal.pgen.1011608.

Several researchers in Manchester have been working on Kabuki syndrome for many years. We work closely with patient organisations, including through the Kabuki information day, and researchers from Manchester are leading the development of Kabuki syndrome clinical guidelines. This work is closely linked with the EpiGenRare node.

Sara Cuvertino

Evgenii Martirosian

Prof Susan Kimber

Prof Siddharth Banka