Advertisement

Molecular Medicine

, Volume 23, Issue 1, pp 196–203 | Cite as

The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy

  • Ding-Sheng Jiang
  • Xin Yi
  • Rui Li
  • Yun-Shu Su
  • Jing Wang
  • Min-Lai Chen
  • Li-Gang Liu
  • Min Hu
  • Cai Cheng
  • Ping Zheng
  • Xue-Hai Zhu
  • Xiang Wei
Research Article

Abstract

Histone modifications play a critical role In the pathological processes of dilated cardiomyopathy (DCM), while the role and expression pattern of histone methyltransferases (HMTs), especially mixed lineage leukemia (MLL) families, in DCM are unclear. To this end, 12 normal and 15 DCM heart samples were included in the present study. A murine cardiac remodeling model was induced by transverse aortic constriction (TAC). Real-time polymerase chain reaction was performed to detect the expression levels of MLL families in the mouse and human left ventricles. The mRNA level of MLL3 was significantly increased in the mouse hearts treated with TAC surgery. Compared with normal hearts, higher mRNA and protein level of MLL3 was detected in the DCM hearts, and its expression level was closely associated with left ventricular end diastolic diameter and left ventricular ejection fraction. However, there was no obvious change in the expression levels of other MLL families (MLL, MLL2, MLL4, MLL5, SETD1A and SETD1B) between control and DCM hearts or remodeled mouse hearts. Furthermore, the dimethylated histone H3 lysine 4 (H3K4me2) but not H3K4me3 was significantly increased in the DCM hearts. The protein levels of Smad3, GATA4 and EGR1, which might be regulated by MLL3, were remarkably elevated in the DCM hearts. Our hitherto unrecognized findings indicate that MLL3 has a potential role in the pathological processes of DCM by regulating H3K4me2 and the expression of Smad3, GATA4 and EGR1.

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81370201, 81600188, 81370264), the National Key Scientific Instrument Special Program of China (2013YQ030923-0607), the Natural Science Foundation of Hubei Province (2016CFB162) and the Fundamental Research Funds for the Central Universities (2042016kf0074).

References

  1. 1.
    Hershberger RE, Hedges DJ, Morales A. (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 10:531–47.CrossRefGoogle Scholar
  2. 2.
    Nguyen AT, et al. (2011) DOT1L regulates dystrophin expression and is critical for cardiac function. Genes Dev. 25:263–74.CrossRefGoogle Scholar
  3. 3.
    Delgado-Olguin P, et al. (2012) Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat. Genet. 44:343–47.CrossRefGoogle Scholar
  4. 4.
    Cho YW, et al. (2007) PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J. Biol. Chem. 282:20395–406.CrossRefGoogle Scholar
  5. 5.
    Bernstein BE, et al. (2002) Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl. Acad. Sci. USA. 99:8695–700.CrossRefGoogle Scholar
  6. 6.
    Lee J, et al. (2008) Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl. Acad. Sci. USA. 105:19229–34.CrossRefGoogle Scholar
  7. 7.
    Ansari KI, Shrestha B, Hussain I, Kasiri S, Mandal SS. (2011) Histone methylases MLL1 and MLL3 coordinate with estrogen receptors in estrogen-mediated HOXB9 expression. Biochemistry. 50:3517–27.CrossRefGoogle Scholar
  8. 8.
    Weirich S, Kudithipudi S, Kycia I, Jeltsch A. (2015) Somatic cancer mutations in the MLL3-SET domain alter the catalytic properties of the enzyme. Clin. Epigenetics. 7:36.CrossRefGoogle Scholar
  9. 9.
    Ansari KI, Mandal SS. (2010) Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 277: 1790–1804.CrossRefGoogle Scholar
  10. 10.
    Sze CC, Shilatifard A. (2016) MLL3/MLL4/COMPASS family on epigenetic regulation of enhancer function and cancer. Cold Spring Harb. Perspect. Med. 6.Google Scholar
  11. 11.
    Lee J, et al. (2009) A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc. Natl. Acad. Sci. USA. 106:8513–18.CrossRefGoogle Scholar
  12. 12.
    Brun ME, et al. (2006) Characterization and expression analysis during embryo development of the mouse ortholog of MLL3. Gene. 371:25–33.CrossRefGoogle Scholar
  13. 13.
    Li WD, et al. (2013) Exome sequencing identifies an MLL3 gene germ line mutation in a pedigree of colorectal cancer and acute myeloid leukemia. Blood. 121:1478–79.CrossRefGoogle Scholar
  14. 14.
    Valekunja UK, et al. (2013) Histone methyltransferase MLL3 contributes to genome-scale circadian transcription. Proc. Natl. Acad. Sci. USA. 110:1554–59.CrossRefGoogle Scholar
  15. 15.
    Ang SY, et al. (2016) KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation. Development. 143:810–21.CrossRefGoogle Scholar
  16. 16.
    Son MJ, et al. (2016) Methyltransferase and demethylase profiling studies during brown adipocyte differentiation. BMB Reports. 49:388–93.CrossRefGoogle Scholar
  17. 17.
    Ford DJ, Dingwall AK. (2015) The cancer COMPASS: navigating the functions of MLL complexes in cancer. Cancer Genet. 208:178–91.CrossRefGoogle Scholar
  18. 18.
    Jiang DS, et al. (2014) IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat. Commun. 5:3303.CrossRefGoogle Scholar
  19. 19.
    Jiang DS, et al. (2014) Signal regulatory protein-alpha protects against cardiac hypertrophy via the disruption of toll-like receptor 4 signaling. Hypertension. 63:96–104.CrossRefGoogle Scholar
  20. 20.
    Jiang DS, et al. (2016) The potential role of lysosome-associated membrane protein 3 (LAMP3) on cardiac remodelling. Am. J. Transl. Res. 8:37–48.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Jiang DS, et al. (2013) Role of interferon regulatory factor 4 in the regulation of pathological cardiac hypertrophy. Hypertension. 61:1193–1202.CrossRefGoogle Scholar
  22. 22.
    Jiang DS, et al. (2014) Interferon regulatory factor 1 is required for cardiac remodeling in response to pressure overload. Hypertension. 64:77–86.CrossRefGoogle Scholar
  23. 23.
    Jiang DS, et al. (2014) Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension. 63:713–22.CrossRefGoogle Scholar
  24. 24.
    Jiang DS, et al. (2014) Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin. Hypertension. 63:119–27.CrossRefGoogle Scholar
  25. 25.
    Kim DH, et al. (2015) Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice. Hepatology. 61:1012–23.CrossRefGoogle Scholar
  26. 26.
    Zhang Q-J, Liu Z-P. (2015) Histone methylations in heart development, congenital and adult heart diseases. Epigenomics. 7:321–30.CrossRefGoogle Scholar
  27. 27.
    Yi X, Jiang XJ, Li XY, Jiang DS. (2015) Histone methyltransferases: novel targets for tumor and developmental defects. Am. J. Transl. Res. 7:2159–75.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Inagawa M, et al. (2013) Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis. Mech. Dev. 130:519–31.CrossRefGoogle Scholar
  29. 29.
    Gidlof O, et al. (2016) Ischemic preconditioning confers epigenetic repression of Mtor and induction of autophagy through G9a-dependent H3K9 dimethylation. J. Am. Heart Assoc. 5(12): e004076.CrossRefGoogle Scholar
  30. 30.
    Sajjad A, et al. (2014) Lysine methyltransferase Smyd2 suppresses p53-dependent cardiomyocyte apoptosis. Biochim. Biophys. Acta. 1843:2556–62.CrossRefGoogle Scholar
  31. 31.
    Zhang QJ, et al. (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J. Clin. Invest. 121:2447–56.CrossRefGoogle Scholar
  32. 32.
    Wan X, et al. (2014) Mll2 controls cardiac lineage differentiation of mouse embryonic stem cells by promoting H3K4me3 deposition at cardiac-specific genes. Stem Cell Rev. 10:643–52.CrossRefGoogle Scholar
  33. 33.
    Lee S, Lee JW, Lee SK. (2012) UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev. Cell. 22:25–37.CrossRefGoogle Scholar
  34. 34.
    Starczynowski DT, Arcipowski KM, Bulic M, Gurbuxani S, Licht JD. (2016) Loss of Mll3 catalytic function promotes aberrant myelopoiesis. PLoS One. 11: e0162515.CrossRefGoogle Scholar
  35. 35.
    Lee S, et al. (2006) Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases. Proc. Natl. Acad. Sci. USA. 103:15392–97.CrossRefGoogle Scholar
  36. 36.
    Chen C, et al. (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell. 25:652–65.CrossRefGoogle Scholar
  37. 37.
    Wang XX, et al. (2011) Somatic mutations of the mixed-lineage leukemia 3 (MLL3) gene in primary breast cancers. Pathol. Oncol. Res. 17:429–33.CrossRefGoogle Scholar
  38. 38.
    Rabello Ddo A, de Moura CA, de Andrade RV, Motoyama AB, Silva FP. (2013) Altered expression of MLL methyltransferase family genes in breast cancer. Int. J. Oncol. 43:653–60.CrossRefGoogle Scholar
  39. 39.
    Li B, et al. (2014) Association of MLL3 expression with prognosis in gastric cancer. Genet. Mol. Res. 13:7513–18.CrossRefGoogle Scholar
  40. 40.
    Kandoth C, et al. (2013) Mutational landscape and significance across 12 major cancer types. Nature. 502:333–39.CrossRefGoogle Scholar
  41. 41.
    Watt AJ, Battle MA, Li J, Duncan SA. (2004) GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc. Natl. Acad. Sci. USA. 101:12573–78.CrossRefGoogle Scholar
  42. 42.
    Bisping E, et al. (2006) Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc. Natl. Acad. Sci. USA. 103:14471–76.CrossRefGoogle Scholar
  43. 43.
    Hsu SC, Chang YT, Chen CC. (2013) Early growth response 1 is an early signal inducing Cav3.2 T-type calcium channels during cardiac hypertrophy. Cardiovasc. Res. 100:222–30.CrossRefGoogle Scholar
  44. 44.
    Bujak M, et al. (2007) Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 116:2127–38.CrossRefGoogle Scholar
  45. 45.
    Saadane N, Alpert L, Chalifour LE. (2000) Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in Egr-1-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 278:H796–805.CrossRefGoogle Scholar
  46. 46.
    Huang XR, et al. (2010) Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling. Hypertension. 55:1165–71.CrossRefGoogle Scholar
  47. 47.
    Liang Q, et al. (2001) The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J. Biol. Chem. 276:30245–53.CrossRefGoogle Scholar
  48. 48.
    Cappuzzello C, et al. (2009) Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients. Physiol. Genomics. 38:233–40.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Ding-Sheng Jiang
    • 1
    • 2
    • 3
  • Xin Yi
    • 4
    • 5
    • 6
  • Rui Li
    • 1
  • Yun-Shu Su
    • 1
  • Jing Wang
    • 1
  • Min-Lai Chen
    • 1
  • Li-Gang Liu
    • 1
  • Min Hu
    • 1
  • Cai Cheng
    • 1
  • Ping Zheng
    • 1
  • Xue-Hai Zhu
    • 1
    • 2
    • 3
  • Xiang Wei
    • 1
    • 2
    • 3
    • 7
  1. 1.Division of Cardiothoracic and Vascular SurgeryHuazhong University of Science and TechnologyWuhanChina
  2. 2.Key Laboratory of Organ Transplantation, Ministry of EducationHuazhong University of Science and TechnologyWuhanChina
  3. 3.Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  4. 4.Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanChina
  5. 5.Cardiovascular Research InstituteWuhan UniversityWuhanChina
  6. 6.Hubei Key Laboratory of CardiologyWuhanChina
  7. 7.Division of Cardiothoracic and Vascular Surgery, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations