Skip to main content

Advertisement

SpringerLink
Log in

Chromatin Modifications in 22q11.2 Deletion Syndrome

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

Chromosome 22q11.2 deletion syndrome is a common inborn error of immunity. The early consequences of thymic hypoplasia are low T cell numbers. Later in life, atopy, autoimmunity, inflammation, and evolving hypogammaglobulinemia can occur and the causes of these features are not understood. This study utilized an unbiased discovery approach to define alterations in histone modifications. Our goal was to identify durable chromatin changes that could influence cell behavior.

Methods

CD4 T cells and CD19 B cells underwent ChIP-seq analysis using antibodies to H3K4me3, H3K27ac, and H4ac. RNA effects were defined in CD4 T cells by RNA-seq. Serum cytokines were examined by Luminex.

Results

Histone marks of transcriptional activation at CD4 T cell promoters and enhancers were globally increased. The promoter activation signature had elements related to T cell activation and inflammation, concordant with effects seen in the transcriptome. B cells, in contrast, had a minimally altered epigenetic landscape in 22q11.2. Both cell types had an “edge” effect with markedly altered chromatin adjacent to the deletion.

Conclusions

People with 22q11.2 deletion have altered CD4 T cell chromatin and a transcriptome concordant with the changes in the epigenome. These effects support a disease model where qualitative changes to T cells occur in addition to quantitative defects that have been well characterized. This study offers unique insight into qualitative differences in the T cells in 22q11.2 deletion, an aspect that has received limited attention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1 
Fig. 2
Fig. 3 
Fig. 4 
Fig. 5
Fig. 6
Fig. 7 

Similar content being viewed by others

Data Availability

Data is available upon request.

Code Availability

N/A.

References

  1. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370(9596):1443–52.

  2. McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.

  3. Piliero LM, Sanford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood. 2004;103(3):1020–5.

  4. Dar N, Gothelf D, Korn D, Frisch A, Weizman A, Michaelovsky E, et al. Thymic and bone marrow output in individuals with 22q11.2 deletion syndrome. Pediatr Res. 2015;77(4):579–85.

  5. Ferrando-Martinez S, Lorente R, Gurbindo D, De Jose MI, Leal M, Munoz-Fernandez MA, et al. Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome. J Pediatr. 2014;164(4):882–9.

  6. Montin D, Marolda A, Licciardi F, Robasto F, Di Cesare S, Ricotti E, et al. Immunophenotype anomalies predict the development of autoimmune cytopenia in 22q11.2 deletion syndrome. J Allergy Clin Immunol Pract. 2019;7(7):2369–76.

  7. Morsheimer M, Brown Whitehorn TF, Heimall J, Sullivan KE. The immune deficiency of chromosome 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173(9):2366–72.

  8. Giardino G, Radwan N, Koletsi P, Morrogh DM, Adams S, Ip W, et al. Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single center. Blood. 2019;133(24):2586–96.

    Article  CAS  Google Scholar 

  9. Herwadkar A, Gennery AR, Moran AS, Haeney MR, Arkwright PD. Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome. J Clin Pathol. 2010;63(2):151–5.

  10. Milner JD, Ward JM, Keane-Myers A, Paul WE. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc Natl Acad Sci USA. 2007;104(2):576–81.

    Article  CAS  Google Scholar 

  11. Campbell JM, Knutsen AP, Becker BA. A 39-year-old father is diagnosed in adulthood as having partial DiGeorge anomaly with a combined T- and B-cell immunodeficiency after diagnosis of the condition in his daughter. Ann Allergy Asthma Immunol. 2008;100(6):620–1.

    Article  Google Scholar 

  12. Pongpruttipan T, Cook JR, Reyes-Mugica M, Spahr JE, Swerdlow SH. Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue associated with granulomatous inflammation in a child with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J Pediatr. 2012;161(5):954–8.

  13. Sood AK, Funkhouser W, Handly B, Weston B, Wu EY. Granulomatous-lymphocytic interstitial lung disease in 22q11.2 deletion syndrome: a case report and literature review. Curr Allergy Asthma Rep. 2018;18(3):14.

  14. Tison BE, Nicholas SK, Abramson SL, Hanson IC, Paul ME, Seeborg FO, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. 2011;128(5):1115–7 e1–3.

  15. Jawad AF, Prak EL, Boyer J, McDonald-McGinn DM, Zackai E, McDonald K, et al. A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (digeorge syndrome/velocardiofacial syndrome). J Clin Immunol. 2011;31(6):927–35.

  16. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.

    Article  Google Scholar 

  17. Zemble R, Luning Prak E, McDonald K, McDonald-McGinn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010;136(3):409–18.

  18. Derfalvi B, Maurer K, McDonald McGinn DM, Zackai E, Meng W, Luning Prak ET, et al. B cell development in chromosome 22q11.2 deletion syndrome. Clin Immunol. 2016;163:1–9.

  19. Burren OS, Rubio Garcia A, Javierre BM, Rainbow DB, Cairns J, Cooper NJ, et al. Chromosome contacts in activated T cells identify autoimmune disease candidate genes. Genome Biol. 2017;18(1):165.

    Article  Google Scholar 

  20. Shi L, Song L, Maurer K, Dou Y, Patel VR, Su C, et al. IL-1 Transcriptional responses to lipopolysaccharides are regulated by a complex of RNA binding proteins. J Immunol. 2020;204(5):1334–44.

    Article  CAS  Google Scholar 

  21. Morou A, Palmer BE, Kaufmann DE. Distinctive features of CD4+ T cell dysfunction in chronic viral infections. Curr Opin HIV AIDS. 2014;9(5):446–51.

    Article  CAS  Google Scholar 

  22. Schulze Zur Wiesch J, Ciuffreda D, Lewis-Ximenez L, Kasprowicz V, Nolan BE, Streeck H, et al. Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med. 2012;209(1):61–75.

  23. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity. 2014;40(2):289–302.

    Article  CAS  Google Scholar 

  24. Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, et al. Age-associated changes in human CD4(+) T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging (Albany NY). 2019;11(21):9234–63.

    Article  CAS  Google Scholar 

  25. Radens CM, Blake D, Jewell P, Barash Y, Lynch KW. Meta-analysis of transcriptomic variation in T-cell populations reveals both variable and consistent signatures of gene expression and splicing. RNA. 2020;26(10):1320–33.

    Article  CAS  Google Scholar 

  26. Weinstein JS, Lezon-Geyda K, Maksimova Y, Craft S, Zhang Y, Su M, et al. Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes. Blood. 2014;124(25):3719–29.

    Article  CAS  Google Scholar 

  27. Javierre BM, Burren OS, Wilder SP, Kreuzhuber R, Hill SM, Sewitz S, et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell. 2016;167(5):1369–84 e19.

  28. Bothma JP, Garcia HG, Ng S, Perry MW, Gregor T, Levine M. Enhancer additivity and non-additivity are determined by enhancer strength in the Drosophila embryo. Elife. 2015;4.

  29. Staple L, Andrews T, McDonald-McGinn D, Zackai E, Sullivan KE. Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease. Pediatr Allergy Immunol. 2005;16(3):226–30.

  30. Di Cesare S, Puliafito P, Ariganello P, Marcovecchio GE, Mandolesi M, Capolino R, et al. Autoimmunity and regulatory T cells in 22q11.2 deletion syndrome patients. Pediatr Allergy Immunol. 2015;26(6):591–4.

  31. Klocperk A, Parackova Z, Bloomfield M, Rataj M, Pokorny J, Unger S, et al. Follicular helper T cells in DiGeorge syndrome. Front Immunol. 2018;9:1730.

    Article  Google Scholar 

  32. Nagakubo D, Swann JB, Birmelin S, Boehm T. Autoimmunity associated with chemically induced thymic dysplasia. Int Immunol. 2017;29(8):385–90.

    Article  CAS  Google Scholar 

  33. Aresvik DM, Lima K, Overland T, Mollnes TE, Abrahamsen TG. Increased levels of interferon-inducible protein 10 (IP-10) in 22q11.2 deletion syndrome. Scand J Immunol. 2016;83(3):188–94.

  34. Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case study: mechanism for increased follicular helper T cell development in activated PI3K delta syndrome. Front Immunol. 2019;10:753.

    Article  CAS  Google Scholar 

  35. Choi JY, Ho JH, Pasoto SG, Bunin V, Kim ST, Carrasco S, et al. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol. 2015;67(4):988–99.

    Article  CAS  Google Scholar 

  36. Shen W, Ye H, Zhang X, Huo L, Shen J, Zhu L, et al. Elevated expansion of follicular helper T cells in peripheral blood from children with acute measles infection. BMC Immunol. 2020;21(1):49.

    Article  CAS  Google Scholar 

  37. Toubi E, Gordon S, Kessel A, Rosner I, Rozenbaum M, Shoenfeld Y, et al. Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J Autoimmun. 2006;27(2):134–9.

    Article  CAS  Google Scholar 

  38. Moisini I, Davidson A. BAFF: a local and systemic target in autoimmune diseases. Clin Exp Immunol. 2009;158(2):155–63.

    Article  CAS  Google Scholar 

  39. Zhang X, Zhang Y, Zhu X, Purmann C, Haney MS, Ward T, et al. Local and global chromatin interactions are altered by large genomic deletions associated with human brain development. Nat Commun. 2018;9(1):5356.

    Article  Google Scholar 

  40. Fulcoli FG, Franzese M, Liu X, Zhang Z, Angelini C, Baldini A. Rebalancing gene haploinsufficiency in vivo by targeting chromatin. Nat Commun. 2016;7:11688.

    Article  CAS  Google Scholar 

  41. de la Morena MT, Eitson JL, Dozmorov IM, Belkaya S, Hoover AR, Anguiano E, et al. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome. Clin Immunol. 2013;147(1):11–22.

  42. Sellier C, Hwang VJ, Dandekar R, Durbin-Johnson B, Charlet-Berguerand N, Ander BP, et al. Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome. PLoS One. 2014;9(8):e103884.

  43. Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(7):2328–37.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the 22q and You Center at CHOP and all the patients and families.

Funding

KES is supported by the Wallace Chair of Pediatrics.

Author information

Authors and Affiliations

  1. Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Zhe Zhang

  2. The Division of Allergy Immunology, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA

    LiHua Shi, Li Song, Kelly Maurer, Xue Zhao & Kathleen E. Sullivan

  3. The Division of Clinical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Elaine H. Zackai, Daniel E. McGinn, T. Blaine Crowley & Donna M. McDonald McGinn

Authors
  1. Zhe Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. LiHua Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelly Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elaine H. Zackai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel E. McGinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T. Blaine Crowley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Donna M. McDonald McGinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kathleen E. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dr. Zhe performed the sequencing analyses.

Dr. Shi made the ChIP-seq libraries and performed data analysis.

Mss. Song, Maurer, and Zhao did cell purification, cell culture, and analyses.

Dr. Zackai participated in experimental design.

Mr. Crowley and Mr. McGinn performed data analyses, clinical data extraction, and sample preparation.

Ms. McGinn and Dr. Sullivan were responsible for the conception, compliance, and execution of the experiments.

Corresponding author

Correspondence to Kathleen E. Sullivan.

Ethics declarations

Ethics Approval

This study was approved by the IRB at The Children’s Hospital of Philadelphia.

Consent to Participate

Patients consented to the participation in this study.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 10858 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Shi, L., Song, L. et al. Chromatin Modifications in 22q11.2 Deletion Syndrome. J Clin Immunol 41, 1853–1864 (2021). https://doi.org/10.1007/s10875-021-01123-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-021-01123-2

Keywords

Search

Navigation