Daura 2021 Neurobiol Dis
| Daura E, Tegelberg S, Yoshihara M, Jackson C, Simonetti F, Aksentjeff K, Ezer S, Hakala P, Katayama S, Kere J, Lehesjoki AE, Joensuu T (2021) Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis. Neurobiol Dis 156:105418. |
Daura Eduard, Tegelberg Saara, Yoshihara Masahito, Jackson Christopher, Simonetti Francesca, Aksentjeff Katri, Ezer Sini, Hakala Paula, Katayama Shintaro, Kere Juha, Lehesjoki Anna-Elina, Joensuu Tarja (2021) Neurobiol Dis
Abstract: Cystatin B (CSTB) acts as an inhibitor of cysteine proteases of the cathepsin family and loss-of-function mutations result in human brain diseases with a genotype-phenotype correlation. In the most severe case, CSTB-deficiency disrupts brain development, and yet the molecular basis of this mechanism is missing. Here, we establish CSTB as a regulator of chromatin structure during neural stem cell renewal and differentiation. Murine neural precursor cells (NPCs) undergo transient proteolytic cleavage of the N-terminal histone H3 tail by cathepsins B and L upon induction of differentiation into neurons and glia. In contrast, CSTB-deficiency triggers premature H3 tail cleavage in undifferentiated self-renewing NPCs and sustained H3 tail proteolysis in differentiating neural cells. This leads to significant transcriptional changes in NPCs, particularly of nuclear-encoded mitochondrial genes. In turn, these transcriptional alterations impair the enhanced mitochondrial respiration that is induced upon neural stem cell differentiation. Collectively, our findings reveal the basis of epigenetic regulation in the molecular pathogenesis of CSTB deficiency.Cystatin B (CSTB) acts as an inhibitor of cysteine proteases of the cathepsin family and loss-of-function mutations result in human brain diseases with a genotype-phenotype correlation. In the most severe case, CSTB-deficiency disrupts brain development, and yet the molecular basis of this mechanism is missing. Here, we establish CSTB as a regulator of chromatin structure during neural stem cell renewal and differentiation. Murine neural precursor cells (NPCs) undergo transient proteolytic cleavage of the N-terminal histone H3 tail by cathepsins B and L upon induction of differentiation into neurons and glia. In contrast, CSTB-deficiency triggers premature H3 tail cleavage in undifferentiated self-renewing NPCs and sustained H3 tail proteolysis in differentiating neural cells. This leads to significant transcriptional changes in NPCs, particularly of nuclear-encoded mitochondrial genes. In turn, these transcriptional alterations impair the enhanced mitochondrial respiration that is induced upon neural stem cell differentiation. Collectively, our findings reveal the basis of epigenetic regulation in the molecular pathogenesis of CSTB deficiency. • Keywords: Cathepsin, Cystatin B, Histone cleavage, Histone clipping, Neural differentiation, Progressive myoclonus epilepsy • Bioblast editor: Reiswig R
On terminology
- For harmonization of terminology on respiratory states and rates, see
- Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. https://doi.org/10.26124/bec:2020-0001.v1
- For harmonization of terminology on respiratory states and rates, see
Labels:
MitoEAGLE terminology
Labels: MiParea: Respiration, nDNA;cell genetics, Genetic knockout;overexpression
Pathology: Neurodegenerative
Organism: Mouse Tissue;cell: Nervous system, Stem cells Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET
Pathway: N, CIV, NS
HRR: Oxygraph-2k
2021-07
