PUBLICATION

Wolf-Hirschhorn Syndrome Candidate 1 (whsc1) Functions as a Tumor Suppressor by Governing Cell Differentiation

Authors

Yu, C., Yao, X., Zhao, L., Wang, P., Zhang, Q., Zhao, C., Yao, S., Wei, Y.

ID

ZDB-PUB-170628-1

Date

2017

Source

Neoplasia (New York, N.Y.) 19: 606-616 (Journal)

Registered Authors

Wang, Ping, Yao, Shaohua, Yu, Chuan

Keywords

none

MeSH Terms

Gene Knockout Techniques
Histone-Lysine N-Methyltransferase/genetics*
Wolf-Hirschhorn Syndrome/genetics
Mutation
Cell Transformation, Neoplastic/genetics
CRISPR-Cas Systems
RNA, Messenger/genetics
RNA, Messenger/metabolism
Genes, Tumor Suppressor*
Gene Expression
Cell Differentiation/genetics*
Animals
Biomarkers
Gene Targeting
Gene Order
Genotype
Genetic Loci
Zebrafish
Phenotype
Embryonic Development/genetics

(all 20)

PubMed

28654864 Full text @ Neoplasia

Abstract

Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is a histone 3 lysine 36 (H3K36) specific methyltransferase that is frequently deleted in Wolf-Hirschhorn syndrome (WHS). Whsc1 is also found mutated in a subgroup of B-cell derived malignant diseases by genomic translocation or point mutation, both of which resulted in hyperactivity of WHSC1 mediated H3K36 methylation and uncontrolled cell proliferation, suggesting that whsc1 functions as an oncogene. However, here we provided evidences to show that whsc1 also has tumor suppressor functions. We used zebrafish as an in vivo model and generated homozygous whsc1 mutant lines via clustered regularly interspaced short palindromic repeats-associated protein Cas9 (CRISPR/Cas9) technology. Then western-blot (WB) and immunofluorescence (IF) were performed to analysis the expression level of H3K36Me2 and H3K36Me3, and we identified the diseased tissue via hematoxylin-eosin (HE) staining, IF staining or immunohistochemistry (IHC). Whsc1 lose-of-function led to significant decrease in di- and tri-methylation of H3K36. A series of WHS related phenotypes were found in whsc1^-/- zebrafish, including growth retardation, neural development defects and heart failure. In addition, loss of function of whsc1 led to defects in the development of swim bladder, possibly through the dis-regulation of key genes in swim bladder organogenesis and inhibition of progenitor cell differentiation, which was correlated with its expression in this organ during embryonic development. At later stage, these whsc1^-/- zebrafishes are inclined to grow tumors in the swim bladder. Our work suggested that whsc1 may function as a tumor suppressor by governing progenitor cell differentiation.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
ccn2a	nsd2^{zf2077/zf2077}	standard conditions	Adult	Not Detected	pleuroperitoneal cavity neoplasm	ISH	Fig. 6
ccn2a	nsd2^{zf2078/zf2078}	standard conditions	Adult	Not Detected	pleuroperitoneal cavity neoplasm	ISH	Fig. 6
ccn2a	WT	standard conditions	Day 4		swim bladder	ISH	Fig. 4
cdh1	nsd2^{zf2077/zf2077}	standard conditions	Adult		pleuroperitoneal cavity neoplasm	IHC	Fig. 6
cdh1	nsd2^{zf2078/zf2078}	standard conditions	Adult		pleuroperitoneal cavity neoplasm	IHC	Fig. 6
fbp2	nsd2^{zf2077/zf2077}	standard conditions	Adult		pleuroperitoneal cavity neoplasm	ISH	Fig. 6
fbp2	nsd2^{zf2078/zf2078}	standard conditions	Adult		pleuroperitoneal cavity neoplasm	ISH	Fig. 6
fbp2	WT	standard conditions	Day 4		swim bladder	ISH	Fig. 4
fzd5	nsd2^{zf2077/zf2077}	standard conditions	Long-pec		whole organism	RTPCR	Fig. 7
fzd5	nsd2^{zf2078/zf2078}	standard conditions	Long-pec		whole organism	RTPCR	Fig. 7

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
nsd2^{zf2077/zf2077}	standard conditions	20-25 somites to Prim-15	third ventricle increased size, abnormal	Fig. 2
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism fzd5 expression increased amount, abnormal	Fig. 7
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism hoxc6a expression increased amount, abnormal	Fig. 7
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism tcf3a expression increased amount, abnormal	Fig. 7
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism tcf3b expression increased amount, abnormal	Fig. 7
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism wnt5b expression increased amount, abnormal	Fig. 7
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism decreased length, abnormal	Fig. 3
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism decreased pigmentation, abnormal	Fig. 3
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism histone H3K36 dimethyltransferase activity decreased occurrence, abnormal	Fig. 1
nsd2^{zf2077/zf2077}	standard conditions	Long-pec	whole organism histone H3K36 trimethyltransferase activity decreased occurrence, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zf2076Tg	Tg2(mnx1:GFP)	Transgenic Insertion
zf2077		Small Deletion	nsd2
zf2078		Small Deletion	nsd2

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Wolf-Hirschhorn syndrome			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
nsd2	CRISPR1-nsd2	CRISPR

Fish

Fish
nsd2^{zf2077/zf2077}
nsd2^{zf2077/zf2077}; zf2076Tg
nsd2^{zf2078/zf2078}
nsd2^{zf2078/zf2078}; zf2076Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Yu et al., 2017 ZDB-PUB-170628-1 PMID:28654864

Wolf-Hirschhorn Syndrome Candidate 1 (whsc1) Functions as a Tumor Suppressor by Governing Cell Differentiation

Yu et al., 2017

ZDB-PUB-170628-1
PMID:28654864