ライフサイエンスコーパス: KDM

1 KDMs have emerged as master regulators of eukaryotic gen

2 ed scintillation proximity assay (SPA) for 3 KDMs: KDM1A (LSD1), KDM3A (JMJD1A), and KDM4A (JMJD2A).

3 rts stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS

4 hylated peptides are first demethylated by a KDM, and a protein methyltransferase (PMT) is added to m

5 ing MS and NMR, that UTY(KDM6C) is an active KDM.

6 n increase in Klemera-Doubal biological age (KDM-BA) and PhenoAge acceleration of 0.26 and 0.49 years

7 anslational modifications than other KMT and KDMs.

8 fying the non-histone substrates of KMTs and KDMs and for studying functions of non-histone lysine me

9 scovery and characterization of the KMTs and KDMs and the methyl modifications they regulate.

10 iants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with deve

11 ting animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited d

12 We discuss the localization of the KMTs and KDMs as well as the distribution of lysine methylation t

13 nally, we discuss the regulation of KMTs and KDMs by proteasomal degradation, posttranscriptional mec

14 We show that KMTs and KDMs that are associated with, or are candidates for, do

15 ogical application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field.

16 dicate that recruitment of specific RDMs and KDMs is required for efficient transcriptional derepress

17 ites enabled identification of new DFP-based KDM inhibitors which are more cytotoxic to cancer cell l

18 s 1-6 are able to simultaneously target both KDM families and have been validated as potential antitu

19 the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using th

20 hat KDM3B, KDM6A, and KDM8 are the candidate KDMs required for osteoblast differentiation.

21 to simultaneously delete Lysine Demethylase (KDM) 5A, 5B and 5C efficiently in vitro and in vivo This

22 umonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily

23 n affecting genes of the lysine demethylase (KDM) family.

24 f the targetable Jumonji lysine demethylase (KDM) family.

25 nt JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site.

26 abolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle

27 ied hepatic demethylases lysine demethylase (KDM)5B and KDM5C as important epigenetic regulators of a

28 sion through the H3K27-specific demethylase (KDM)6B.

29 the Jumonji family of histone demethylases (KDM and JMJD), which is known to impact gene expression.

30 transferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene e

31 ferent types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed and colo

32 methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation.

33 The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are cu

34 analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and disea

35 ransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene e

36 The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenase

37 Histone lysine demethylases (KDMs) are epigenetic enzymes that can remove both repres

38 Jumonji C (JmjC) lysine demethylases (KDMs) are Fe(II)-dependent hydroxylases that catalyze th

39 Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene exp

40 Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regul

41 lyses implicate histone lysine demethylases (KDMs) as its targets.

42 The lysine demethylases (KDMs) catalyze the demethylation of lysine residues on h

43 Lysine demethylases (KDMs) catalyze the oxidative removal of the methyl group

44 transferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mes

45 transferases (KMTs) and lysine demethylases (KDMs) that regulate them.

46 enty years ago, histone lysine demethylases (KDMs) were discovered.

47 uccessfully apply it to lysine demethylases (KDMs) which catalyze the removal of methyl groups from l

48 geting histone N-methyl-lysine demethylases (KDMs) with small molecules both for the generation of pr

49 transferases (KMTs) and lysine demethylases (KDMs), respectively-are frequently mutated and dysregula

50 iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDM

51 imited homology to JmjC lysine demethylases (KDMs).

52 stone N(epsilon)-methyl lysine-demethylases (KDMs) and hydroxylases catalysing formation of stable al

53 Histone Lys-specific demethylases (KDMs) play a key role in many biological processes throu

54 e comparable to that of the flavin-dependent KDM LSD1.

55 Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor develo

56 rably less active or inactive against eleven KDMs - 1A, 3A, 3B, 4A-E, 5A, 5B and 6B.

57 GrimAge, and ZS in cancer survivors, and for KDM-BA, PhenoAge, and ZS in controls (Cox regression).

58 ifferent KDMs has been a major challenge for KDM inhibitor development.

59 imal therapeutic options to be developed for KDM-related diseases in the years ahead.

60 bly, the preferred sequence requirements for KDM and RDM activity vary even with the same JmjC enzyme

61 n optimized continuous fluorescent assay for KDMs that detects formaldehyde production during demethy

62 JMJD5 is reported to have KDM activity, but has been shown to catalyse C-3 hydroxy

63 The results expand the set of human KDMs and will be of use in developing selective KDM inhi

64 s into the functional heterogeneity of human KDMs are limited, necessitating the development of chemi

65 rification and kinetic analysis of the human KDMs JMJD2A and JMJD2D using these methods yielded activ

66 in the unfavourable SDH group had increased KDM-BA and phenotypic age acceleration.

67 new chemical scaffold capable of inhibiting KDM enzymes, globally changing histone modification prof

68 milies of N-methyl-lysine demethylases (JmjC KDMs, KDM2-7), focusing on the academic and patent liter

69 he 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-met

70 ing that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histo

71 ogical importance, recombinant forms of JmjC KDMs generally display low enzymatic activity and have r

72 bed here is broadly applicable to other JmjC KDMs, facilitating their biochemical characterization an

73 urification scheme for Strep(II)-tagged JmjC KDMs that minimizes contamination by transition state me

74 The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxyge

75 substrate-competitive inhibitors of the JmjC KDMs.

76 te that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor

77 ights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible appro

78 mall molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes,

79 h offspring using the Klemera-Doubal method (KDM)-based BA at age 32 and potential familial life-cour

80 estimated by the Klemera and Doubal method (KDM-BA), phenotypic age (PhenoAge), and subjective age (

81 ic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B.

82 We conclude that alterations of KDM family members represent a disease-driving mechanism

83 5.9% increase per standard deviation [SD] of KDM-BA acceleration, 95% confidence intervals [CI]: 3.3%

84 use ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably p

85 l drug targets; small-molecule inhibitors of KDMs are in the clinical pipeline for the treatment of h

86 ys have been developed to find inhibitors of KDMs, most of which are fluorescence-based assays.

87 However, the role of KDMs in inflammatory responses to oral bacterial infecti

88 largely from the inhibition of a sub-set of KDMs.

89 esulting in pan inhibition of a subfamily of KDMs.

90 osure and age, sex, deprivation, and diet on KDM-BA and PhenoAge acceleration.

91 ur analysis identified that LSD1 is the only KDM required for myogenic differentiation and that KDM3B

92 onal analysis for an entire family of KMT or KDM enzymes has not been performed.

93 s of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E i

94 ld selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar con

95 ned and synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1-6 by coupling the skeleton of tranylcy

96 Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest spec

97 st coupled assays are suitable for screening KDMs in 384-well format (Z' factors of 0.70-0.80), facil

98 s and will be of use in developing selective KDM inhibitors.

99 marks that are subject to removal by several KDM subfamilies which are inhibited by DFP in cell-free

100 P inhibits the demethylase activities of six KDMs - 2A, 2B, 5C, 6A, 7A and 7B - with low micromolar I

101 The KDM that is most sensitive to DFP, KDM6A, has an IC(50)

102 The docked poses adopted by DFP at the KDM active sites enabled identification of new DFP-based

103 ecently identified, including members of the KDM histone demethylase family.

104 se (KDM) enzymes are encoded by genes of the KDM superfamily.

105 overs these key relationships related to the KDM field with the awareness that numerous laboratories

106 iological age from clinical traits using the KDM-BA and PhenoAge algorithms.

107 ginine-methylated and sequences in which the KDM's methylated target lysine is substituted for a meth

108 and structural studies which are relevant to KDM inhibitor development.