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PDBsum entry 2x0l
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Transcription
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PDB id
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2x0l
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Contents |
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670 a.a.
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133 a.a.
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16 a.a.
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References listed in PDB file
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Key reference
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Title
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Alternative splicing of the histone demethylase lsd1/kdm1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system.
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Authors
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C.Zibetti,
A.Adamo,
C.Binda,
F.Forneris,
E.Toffolo,
C.Verpelli,
E.Ginelli,
A.Mattevi,
C.Sala,
E.Battaglioli.
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Ref.
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J Neurosci, 2010,
30,
2521-2532.
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PubMed id
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Abstract
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A variety of chromatin remodeling complexes are thought to orchestrate
transcriptional programs that lead neuronal precursors from earliest commitment
to terminal differentiation. Here we show that mammalian neurons have a
specialized chromatin remodeling enzyme arising from a neurospecific splice
variant of LSD1/KDM1, histone lysine specific demethylase 1, whose demethylase
activity on Lys4 of histone H3 has been related to gene repression. We found
that alternative splicing of LSD1 transcript generates four full-length isoforms
from combinatorial retention of two identified exons: the 4 aa exon E8a is
internal to the amine oxidase domain, and its inclusion is restricted to the
nervous system. Remarkably, the expression of LSD1 splice variants is
dynamically regulated throughout cortical development, particularly during
perinatal stages, with a progressive increase of LSD1 neurospecific isoforms
over the ubiquitous ones. Notably, the same LSD1 splice dynamics can be fairly
recapitulated in cultured cortical neurons. Functionally, LSD1 isoforms display
in vitro a comparable demethylase activity, yet the inclusion of the sole exon
E8a reduces LSD1 repressor activity on a reporter gene. Additional distinction
among isoforms is supported by the knockdown of neurospecific variants in
cortical neurons resulting in the inhibition of neurite maturation, whereas
overexpression of the same variants enhances it. Instead, perturbation of LSD1
isoforms that are devoid of the neurospecific exon elicits no morphogenic
effect. Collectively, results demonstrate that the arousal of neuronal LSD1
isoforms pacemakes early neurite morphogenesis, conferring a neurospecific
function to LSD1 epigenetic activity.
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