Epigenetic modifications instruct stem cells

Functionally specialized areas of the neocortex are formed through a gradient of gene expression in the neuroepithelium. This relies on a time-dependent cell fate decision of precursor cells. 

We have highlighted the contribution of histone methylation in the neuronal specification of upper layer neurons in an AF9- (Buttner et al. 2010) and in DOT1L-mutant mice (Franz et al. 2019).

AF9-interaction partner DOT1L regulates the expression of the transcription factor TBR1 through methylation of Histone H3 at position K79. We highlighted that DOT1L activity prevents the activation of the ER-stress related transcriptional program in vitro (Roidl et al. 2016). 

Our interests further elucidated the transcriptional network of AF9 and DOT1L and their implication in cortical, hippocampal, cerebellar (Bovio et al. 2019) and spinal cord (Gray de Cristoforis et al. 2020) development in vivo and in vitro. We are currently using ChIP-protocols (Bovio et al. 2018) to characterise in detail the distribution of H3K79 methylation in these various neuroanatomical locations to establish this histone mark as essential in balancing proliferation and differentiation of neural stem cells. 

As part of the DFG-funded research training group 2344 "MeInBio" we explore histone modifications and transcriptional regulation through DOT1L in mouse embryonic stem cells (mESCs), in small cell samples and on single cell level. H3K79me2 as readout of DOT1L's enzymatic activity is, together with H3K27ac, informative for differentiation of mESCs as we showed by quantitative ChIP-seq. Furthermore, we here show that DOT1L regulates accessibility of SOX2 to enhancer regions (Ferrari et al. 2020). We showed that DOT1L regulates metabolic programs (Appiah et al. 2022) and is necessary for proper expression levels of transcription factors regulating development of the hippocampal cornu ammonis and dentate gyrus (Salas et al. 2021).

Further reading:

Treppner M, Salas-Bastos A, Hess M, Lenz S, Vogel T, Binder H.Synthetic single cell RNA sequencing data from small pilot studies using deep generative models. Sci Rep. 11(1):9403-11. (2021). 

Kosinsky RL, Wegwitz F, Hellbach N, Dobbelstein M, Mansouri A, Vogel T, Begus-Nahrmann Y, Johnsen SA (2015) Usp22 deficiency impairs intestinal epithelial lineage specification in vivo. Oncotarget 6(35):37906-18. 

Karpiuk O, Najafova Z, Kramer F, Hennion M, Galonska C, König A, Snaidero N, Vogel T, Shchebet TA, Begus-Nahrmann Y, Kassem M, Simons M, Shcherbata H, Beissbarth T, Johnsen SA (2012) The histone H2B monoubiquitination regulatory pathway is required for differentiation of multipotent stem cells. Molecular Cell 46(5): 705–713.

Vogel T, Gruss P. Expression of Leukaemia associated transcription factor Af9/Mllt3 in the cerebral cortex of the mouse. Gene Expr Patterns. 2009 Feb;9(2):83-93. 

Britanova O, de Juan Romero C, Cheung A, Kwan KY, Schwark M, Gyorgy A, Vogel T, Akopov S, Mitkovski M, Agoston D, Sestan N, Molnár Z, Tarabykin V. Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron. 2008 Feb 7;57(3):378-92. 

Vogel T, Stoykova A, Gruss P (2006) Differential expression of polycomb repression complex 1 (PRC1) members in the developing mouse brain reveals multiple complexes. Dev Dyn 235: 2574-2585.