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PDBsum entry 2kgi
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Metal binding protein
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PDB id
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2kgi
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References listed in PDB file
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Key reference
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Title
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Haematopoietic malignancies caused by dysregulation of a chromatin-Binding phd finger.
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Authors
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G.G.Wang,
J.Song,
Z.Wang,
H.L.Dormann,
F.Casadio,
H.Li,
J.L.Luo,
D.J.Patel,
C.D.Allis.
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Ref.
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Nature, 2009,
459,
847-851.
[DOI no: ]
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PubMed id
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Abstract
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Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical
component in regulating gene expression, epigenetic states, and cellular
identities1. The biological meaning of H3K4me is interpreted by conserved
modules including plant homeodomain (PHD) fingers that recognize varied H3K4me
states. The dysregulation of PHD fingers has been implicated in several human
diseases, including cancers and immune or neurological disorders. Here we report
that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the
carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2),
to a common fusion partner nucleoporin-98 (NUP98) as identified in human
leukaemias, generated potent oncoproteins that arrested haematopoietic
differentiation and induced acute myeloid leukaemia in murine models. In these
processes, a PHD finger that specifically recognizes H3K4me3/2 marks was
essential for leukaemogenesis. Mutations in PHD fingers that abrogated H3K4me3
binding also abolished leukaemic transformation. NUP98-PHD fusion prevented the
differentiation-associated removal of H3K4me3 at many loci encoding
lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1),
and enforced their active gene transcription in murine haematopoietic
stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin
boundary factors', dominating over polycomb-mediated gene silencing to 'lock'
developmentally critical loci into an active chromatin state (H3K4me3 with
induced histone acetylation), a state that defined leukaemia stem cells.
Collectively, our studies represent, to our knowledge, the first report that
deregulation of the PHD finger, an 'effector' of specific histone modification,
perturbs the epigenetic dynamics on developmentally critical loci,
catastrophizes cellular fate decision-making, and even causes oncogenesis during
mammalian development.
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Figure 2.
Figure 2: JARID1A-PHD3, an essential motif for NJL-mediated
leukaemia, specifically recognizes H3K4me3/2 marks. a,
Capability of JARID1A-PHD3, PHF23-PHD and JARID1A-PHD1 (the
first PHD finger of JARID1A; Supplementary Fig. 1) to interact
with H3 peptides containing different states of Lys methylation,
in a peptide pull-down assay. JARID1A-PHD1 interacted with
H3K4me0 as BHC80-PHD^11. aa, amino acids. b, The crystal
structure of JARID1A-PHD3 (cyan) complexed with H3K4me3 peptide
(yellow), and a close-up view of the H3K4me3-binding channel
(inset) formed by two orthogonally aligned Trp residues. The
numeration of JARID1A-PHD3 and H3 residues is shown in red and
black, respectively. Protein Data Bank accession number, 3GL6.
c, Capability of wild-type (WT) or mutant JARID1A-PHD3 to bind
to H3K4me3/2. d, Co-immunoprecipitation showing that NJL
containing the wild-type, but not mutant (W1625A) PHD finger,
associated with H3K4me3 or H3 in transiently transfected 293
cells.
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Figure 4.
Figure 4: The H3K4me3/2 engagement by NUP98–JARID1A perturbs
the epigenetic state of developmentally critical loci during
haematopoiesis. a, The impact of mutations on Flag–NJL
binding to HOXA9 in 293 cells. WT, wild type. b, Immunoblot of
haematopoietic progenitors 10 days after transduction of vector,
wild-type or mutant NJL. Phosphorylated c-Kit (P-c-Kit) is a
marker of mast cells. Actin is shown as a loading control. c,
ChIP for Hoxa9 promoter-associated NUP98-fusion proteins (3  Flag-tagged)
and H3K4me3 in marrow progenitors 10 days after transduction. d,
e, Transforming capacities after introducing mutation to NJL (d)
or those by NUP98–PHF23 (e) or after replacing JARID1A-PHD3
with another PHD finger that engages either H3K4me3/2 or
H3K4me0. The total progenitor number was counted at day 1, 10,
25 and 40. f–h ChIP for Suz12 (f), Mll2-binding to Hoxa9/a11
(g), and Hoxa9-associated H3 acetylation (h) in marrow
progenitors 15 days after transduction of vector or NJL. Error
bar indicates s.d.; n = 3; *P < 0.05, **P < 0.005, ***P < 10^-4
and *****P < 10^-6. i, A scheme showing that NUP98–PHD fusion
acts as a boundary factor and prevents the spreading of polycomb
factors from Hoxa13/a11 to Hoxa9, thus inhibiting H3K4me3
removal and H3K27me3 addition during haematopoiesis.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nature
(2009,
459,
847-851)
copyright 2009.
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