Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jan 25:3:1.
doi: 10.3389/fonc.2013.00001. eCollection 2013.

MYCN and the epigenome

Stanley He  1 , Zhihui Liu, Doo-Yi Oh, Carol J Thiele
Affiliations

MYCN and the epigenome

Stanley He et al. Front Oncol. .

Abstract

It is well known that Neuroblastoma (NB) patients whose tumors have an undifferentiated histology and a transcriptome enriched in cell cycle genes have a worse prognosis. This contrasts with the good prognoses of patients whose tumors have histologic evidence of differentiation and a transcriptome enriched in differentiation genes. Tumor cell lines from poor prognosis, high-risk patients contain a number of genetic alterations, including amplification of MYCN, 1pLOH, and unbalanced 11q or gains of Chr 17 and 7, and exhibit uncontrolled growth and an undifferentiated phenotype in in vitro culture. Yet treatment of such NB cell lines with retinoic acid results in growth control and induction of differentiation. This indicates that the signaling pathways that regulate cell growth and differentiation are not functionally lost but dysregulated. Agents such as retinoic acid normalize the signaling pathways and impose growth control and induction of differentiation. Recent studies in embryonic stem cells indicate that polycomb repressor complex proteins (PRC1 and PRC2) play a major role in regulating stem cell lineage specification and coordinating the shift from a transcriptome that supports self-renewal or growth to one that specifies lineage and controls growth. We have shown that in NB, the PRC2 complex is elevated in undifferentiated NB tumors and functions to suppress a number of tumor suppressor genes. This study will review the role of MYC genes in regulating the epigenome in normal development and explore how this role may be altered during tumorigenesis.

Keywords: EZH2; HAT; HDAC; MYCN; RNA polymerase II; epigenetics; nucleosome; transcriptional activation.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Diagram of MYC functional regions. In the region of the transcriptional activation domain (TAD) the MYC Box II (MBII) binds TRRAP containing complexes of proteins that may also contain GCN5. It is also felt that p-TEFb, Tip60, and a number of other transcriptional regulatory factors can bind to this region. Determinants of which factors bind remain to be resolved. The bHLH region binds E-box containing regions of DNA. MYC dimerizes with other bHLH containing transcription factors via a carboxy-terminal leucine zipper (Zip) region. While MYC recruits HATs such as GCN5 and CBP/p300 which are known to acetylate lysine residue on histone tails, these HATs are also known to acetylate (Ac) MYC which affects its stability by blocking or competing with ubiquitin ligases that _target MYC for degradation.
FIGURE 2
FIGURE 2
(A) Compacted heterochromatin is characterized by specific methylation of H3K9 and H3K27 is often correlated with decreased transcription. The EZH2 component of PRC2 contains the H3K27methylase while EHMT2 or G9a contains the H3K9 methylase. The methylation status of these amino acids is regulated by demethylases such as LSD1, JMJD2, and UTX. The subsequent acetylation (Ac) of H3K9 by GCN5 and H3K27 by CBP/p300 are associated with relief of gene suppression. (B) MYC recruits TRRAP to _target loci to mediate MYC binding to histone acetyltransferases (HATs). Recruited HATs acetylate histone components to promote transcription. Conversely, MAD recruits Sin3 to _target loci to mediate MAD binding to histone deacetylases (HDACs). Histone deacetylation allows for methylation events leading to transcriptional silencing. (C) Via TRRAP, MYC is able to recruit HATs GCN5, TIP60, and CBP/p300 to _target loci to relax the nucleosomal barrier making DNA more accessible to transcriptional machinery and making the nucleosome more permissive for transcription. (D) MYC can also bind to TBP suggesting it can recruit elements of the transcriptional pre-initiation complex to initiate transcription. To maintain transcription MYC recruits p-TEFb and BRD4 to catalyze promoter pause release and transcriptional elongation. BRD4, as well as GCN5 and CBP, have bromodomains (Br) that recognize acetyl-lysines which has proven necessary for proper function.
FIGURE 3
FIGURE 3
MYCN influences global chromatin structure. (A) The SK-N-AS cell line contains a single copy of MYCN and does not express significant quantities. Upon transfection of SK-N-AS with MYCN (14-2, Vector control: 8B), one can see enlarged nuclei in high MYCN expressing cells (nuclei are stained with DNA binding dye DAPI). (B) Measurements indicate a twofold increase in nuclear size.
FIGURE 4
FIGURE 4
Decrease of EZH2 affects NB cell growth and induces the neurites (Wang et al., 2012). (A) Cell survival in KCNR cells after a 3-day infection with EZH2 or non-_target shRNA lentivirus was assessed using a Cell-Titer Blue assay (left). The percentage of surviving cells was normalized by the absorbance value of the non-_target shRNA-infected cells (control). Representative images (×200) of the non-_target shRNA-infected cells (ctrl, middle), EZH2 shRNA–infected cells (EZH2 shRNA, right). (B) KCNR cells were treated with different concentration of DZNep for 96 h. MTS assay was used to detected cell survival (left). The percentage of surviving cells was normalized by the absorbance value of the non-treated cells. Representative images (×200) of the non-treated cells (ctrl, middle) and 0.5 μmol/L DZNep-treated cells (DZNep 0.5 μmol/L, right). (C) KCNR cells were treated with different concentration of DZNep for 96 h. The cells were stained with propidium iodide and analyzed by flow cytometry. The data showed percentage of events in sub-G1, G1, and S/G2–M phase. (D) Caspase 3/7 activities were assessed after 48 h with different concentration of DZNep in KCNR cells. The percentage of caspase 3/7 activity was graphed after normalization to non-treated cells. (E) KCNR cells were treated with 5 μmol/L DZNep in the absence or presence of 100 μmol/L pan caspase inhibitor, Z-VAD-FMK, for 72 h. The percentage of surviving cells was graphed after normalization to untreated control. (F) Mice were treated with or without DZNep (2.5 mg/kg) twice a day, 3 days per week for 4 weeks. The mean tumor volumes are plotted using the SEM. The time points with significant differences (P < 0.05) are indicated with an asterisk. Adapted from Wang et al. (2012). © 2012 American Association for Cancer Research.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Allard S., Utley R. T., Savard J., Clarke A., Grant P., Brandl C. J., et al. (1999). NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM-related cofactor Tra1p. EMBO J. 18 5108–5119 - PMC - PubMed
    1. Ayer D. E. (1999). Histone deacetylases: transcriptional repression with SINers and NuRDs. Trends Cell Biol. 9 193–198 - PubMed
    1. Bernstein B. E., Meissner A., Lander E. S. (2007). The mammalian epigenome. Cell 128 669–681 - PubMed
    1. Bintu L., Ishibashi T., Lander E. S. (2012). Nucleosomal elements that control the topography of the barrier to transcription. Cell 151 738–749 - PMC - PubMed
    1. Bisgrove D. A., Mahmoudi T., Henklein P., Verdin E. (2007). Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc. Natl. Acad. Sci. U.S.A. 104 13690–13695 - PMC - PubMed

LinkOut - more resources

  NODES
Association 1
HOME 2
Javascript 1
mac 1
os 23
text 12
twitter 2
web 5