A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers

Vrba, Lukas; Garbe, James C.; Stampfer, Martha R.; Futscher, Bernard W.

doi:10.1080/15592294.2015.1106673

Title: A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers

Abstract

Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting 2 critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from 4 individuals. A total of 277 genes consistently changed in cells that transitioned from post-stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the gene expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the downregulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen inmore »« less

Authors:

Vrba, Lukas ^[1]; Garbe, James C. ^[2]; Stampfer, Martha R. ^[3]; Futscher, Bernard W. ^[1]

Univ. of Arizona, Tucson, AZ (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Univ. of Arizona, Tucson, AZ (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Publication Date:: Mon Oct 19 00:00:00 EDT 2015

Research Org.:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1257370

Alternate Identifier(s):: OSTI ID: 1407279

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: Epigenetics

Additional Journal Information:: Journal Volume: 10; Journal Issue: 11; Journal ID: ISSN 1559-2294

Publisher:: Taylor & Francis

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; breast cancer; DNA methylation; epigenetics; immortality; HMEC; lncRNA; lincRNA; MORT; mammary epithelia; ncRNA; ZNF667-AS1

Citation Formats


                    Vrba, Lukas, Garbe, James C., Stampfer, Martha R., and Futscher, Bernard W. A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers.  United States: N. p., 2015. 
Web.  doi:10.1080/15592294.2015.1106673.

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                    Vrba, Lukas, Garbe, James C., Stampfer, Martha R., & Futscher, Bernard W. A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers.  United States.  https://doi.org/10.1080/15592294.2015.1106673

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                    Vrba, Lukas, Garbe, James C., Stampfer, Martha R., and Futscher, Bernard W. Mon .  
"A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers".  United States.  https://doi.org/10.1080/15592294.2015.1106673.  https://www.osti.gov/servlets/purl/1257370.

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@article{osti_1257370,

  title        = {A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers},

  author       = {Vrba, Lukas and Garbe, James C. and Stampfer, Martha R. and Futscher, Bernard W.},

  abstractNote = {Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting 2 critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from 4 individuals. A total of 277 genes consistently changed in cells that transitioned from post-stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the gene expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the downregulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen in human breast cancer cell lines and in a majority of human breast tumor tissues. The functional importance of DNA hypermethylation in MORT gene silencing is supported by the ability of 5-aza-2'-deoxycytidine to reactivate MORT expression. Analysis of TCGA data revealed deregulation of MORT expression due to DNA hypermethylation in 15 out of the 17 most common human cancers. The epigenetic silencing of MORT in a large majority of the common human cancers suggests a potential fundamental role in cellular immortalization during human carcinogenesis.},

  doi          = {10.1080/15592294.2015.1106673},

  journal      = {Epigenetics},

  number       = 11,

  volume       = 10,

  place        = {United States},

  year         = {Mon Oct 19 00:00:00 EDT 2015},

  month        = {Mon Oct 19 00:00:00 EDT 2015}

}

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Frontiers in Oncology, Vol. 6
DOI: 10.3389/fonc.2016.00132

Integrative analysis of the contribution of mRNAs and long non‑coding RNAs to the pathogenesis of asthma
journal, July 2019

Liu, Xiaochuang; Zhang, Yanyan; Jiang, Hui
Molecular Medicine Reports
DOI: 10.3892/mmr.2019.10511

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Background: Human mammary epithelial cells (HMEC) overcome two well-characterized genetic and epigenetic barriers as they progress from primary cells to fully immortalized cell lines in vitro. Finite lifespan HMEC overcome an Rb-mediated stress-associated senescence barrier (stasis), and a stringent, telomere-length dependent, barrier (agonescence or crisis, depending on p53 status). HMEC that have overcome the second senescence barrier are immortalized. Methods: We have characterized pre-stasis, post-selection (post-stasis, with p16 silenced), and fully immortalized HMEC by transcription profiling and RT-PCR. Four pre-stasis and seven post-selection HMEC samples, along with 10 representatives of fully immortalized breast epithelial cell lines, were profiled using Affymetrixmore »« less
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