Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Seung Woo Cho; Jin Xu; Ruping Sun; Maxwell R. Mumbach; Ava C. Carter; Y. Grace Chen; Kathryn E. Yost; Jeewon Kim; Jing He; Stephanie A. Nevins; Suet Feung Chin; Carlos Caldas; S. John Liu; Max A. Horlbeck; Daniel A. Lim; Jonathan S. Weissman; Christina Curtis; Howard Y. Chang

doi:10.1016/j.cell.2018.03.068

Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Seung Woo Cho, Jin Xu, Ruping Sun, Maxwell R. Mumbach, Ava C. Carter, Y. Grace Chen, Kathryn E. Yost, Jeewon Kim, Jing He, Stephanie A. Nevins, Suet Feung Chin, Carlos Caldas, S. John Liu, Max A. Horlbeck, Daniel A. Lim, Jonathan S. Weissman, Christina Curtis, Howard Y. Chang

Research output: Contribution to journal › Article › peer-review

312 Scopus citations

Abstract

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements. Recurrent mutations in human cancer are found encompassing the promotor for the lncRNA gene PVT1, which regulates MYC transcription via promoter competition for a shared set of enhancers.

Original language	English (US)
Pages (from-to)	1398-1412.e22
Journal	Cell
Volume	173
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2018.03.068
State	Published - May 31 2018
Externally published	Yes

Bibliographical note

Funding Information:
We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute , Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH ( R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute.

Funding Information:
We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute, Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH (R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

CRISPRi
MYC
PVT1
enhancer
lncRNA
promoter
topological domains
transcriptional regulation
tumor suppressor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cho, S. W., Xu, J., Sun, R., Mumbach, M. R., Carter, A. C., Chen, Y. G., Yost, K. E., Kim, J., He, J., Nevins, S. A., Chin, S. F., Caldas, C., Liu, S. J., Horlbeck, M. A., Lim, D. A., Weissman, J. S., Curtis, C., & Chang, H. Y. (2018). Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element. Cell, 173(6), 1398-1412.e22. https://doi.org/10.1016/j.cell.2018.03.068

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title = "Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element",

abstract = "Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements. Recurrent mutations in human cancer are found encompassing the promotor for the lncRNA gene PVT1, which regulates MYC transcription via promoter competition for a shared set of enhancers.",

keywords = "CRISPRi, MYC, PVT1, enhancer, lncRNA, promoter, topological domains, transcriptional regulation, tumor suppressor",

author = "Cho, {Seung Woo} and Jin Xu and Ruping Sun and Mumbach, {Maxwell R.} and Carter, {Ava C.} and Chen, {Y. Grace} and Yost, {Kathryn E.} and Jeewon Kim and Jing He and Nevins, {Stephanie A.} and Chin, {Suet Feung} and Carlos Caldas and Liu, {S. John} and Horlbeck, {Max A.} and Lim, {Daniel A.} and Weissman, {Jonathan S.} and Christina Curtis and Chang, {Howard Y.}",

note = "Funding Information: We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute , Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH ( R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute, Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH (R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.cell.2018.03.068",

language = "English (US)",

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AU - Cho, Seung Woo

AU - Xu, Jin

AU - Sun, Ruping

AU - Mumbach, Maxwell R.

AU - Carter, Ava C.

AU - Chen, Y. Grace

AU - Yost, Kathryn E.

AU - Kim, Jeewon

AU - He, Jing

AU - Nevins, Stephanie A.

AU - Chin, Suet Feung

AU - Caldas, Carlos

AU - Liu, S. John

AU - Horlbeck, Max A.

AU - Lim, Daniel A.

AU - Weissman, Jonathan S.

AU - Curtis, Christina

AU - Chang, Howard Y.

N1 - Funding Information: We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute , Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH ( R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank members of the Chang lab for helpful discussions and assistance. We thank Seung K. Kim for access to fluorescence-activated cell sorting (FACS), the Transgenic, Knockout, and Tumor Model Center of Stanford Cancer Institute, Hokyung K. Chung for her help in microscopy imaging, and Hye Mi Jung for advice on the scientific illustrations. This work was supported by the NIH (R35-CA209919 and P50-HG007735 to H.Y.C; 1R01- NS091544 and R21-NS101395 to D.A.L.; U01-CA217882 and R01-DA036858 to J.S.W.; and S10OD018220 to the Stanford Functional Genomics Facility). J.S.W. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2018 Elsevier Inc.

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N2 - Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements. Recurrent mutations in human cancer are found encompassing the promotor for the lncRNA gene PVT1, which regulates MYC transcription via promoter competition for a shared set of enhancers.

AB - Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements. Recurrent mutations in human cancer are found encompassing the promotor for the lncRNA gene PVT1, which regulates MYC transcription via promoter competition for a shared set of enhancers.

KW - CRISPRi

KW - MYC

KW - PVT1

KW - enhancer

KW - lncRNA

KW - promoter

KW - topological domains

KW - transcriptional regulation

KW - tumor suppressor

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Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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