The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis

Fewings, Nicole; Gatt, Prudence N.; McKay, Fiona C.; Parnell, Grant P; Schibeci, Stephen D.; Edwards, Jarem; Basuki, M.A.I.; Goldinger, Anita; Fabis-Pedrini, Marzena J.; Kermode, Allan G.; Manrique, Clara P.; McCauley, Jacob L.; Nickles, Dorothee; Baranzini, Sergio E.; Burke, Therese; Vucic, Steve; Stewart, Graeme J.; Booth, David R.

doi:10.1016/j.jaut.2016.12.006

Cited by 29 publications

(37 citation statements)

References 51 publications

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“…The second differentiating cell type was the non-classical monocyte (CD16+); this was significantly decreased in ODC compared with HC but not in CIS. This finding is supported by recent publications analysing CD16+ monocytes and their gene expression in peripheral blood and the CSF of people with MS [16,17]. CD16+ monocytes from MS patients tend to have increased surface expression of activation markers and respond more robustly with inflammatory cytokine production to in vitro stimulation compared with cells from healthy controls [18,19].…”

Section: Discussionsupporting

confidence: 66%

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Trend

Jones

Geldenhuys

et al. 2017

IJMS

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It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.

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Section: Discussionsupporting

confidence: 66%

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Trend

Jones

Geldenhuys

et al. 2017

IJMS

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“…This region loops to the promoter of the short isoform of ZMIZ1 in EBV EBNA2+ Ramos cells. ZMIZ1 expression levels are three-fold lower in EBV EBNA2+ Ramos cells compared to uninfected Ramos cells, consistent with a previous report by Fewing et al describing decreased ZMIZ1 protein expression in MS patient blood samples (Fewings et al 2017). As a second example, we observed strong (>2fold) allele-dependent EBNA2 binding in GM12878 cells to a vitiligo associated variant (rs867234) located within the promoter of the upregulated EBNA2 DEG CD80 (Fig.…”

Section: Allele-dependent Ebna2 Mechanisms At Autoimmune-disease Risksupporting

confidence: 91%

Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci

Hong

Donmez

Miller

et al. 2020

Preprint

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The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein-Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we demonstrated that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding, in a B cell line that was 1) uninfected, 2) infected with a strain of EBV lacking EBNA2, or 3) infected with a strain that expresses EBNA2.We identified >400 EBNA2-dependent differentially expressed human genes and >4,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >3,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >2,000 regions where EBNA2 altered chromatin looping interactions. Importantly, autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events.We present examples of autoimmune risk genotype-dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1 and CD80. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

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“…A further protein of interest in regard to myelination is the Zinc finger MIZ domain‐containing protein 1 (Zmiz1), the top (8x) up‐regulated protein in GM+. This provides a new molecular phenotype of multiple sclerosis patients (Fewings et al, ) and is crucial for Notch and other signalling pathways regulating the balance between proliferation and differentiation in many cell types (Beliakoff et al, ; Li et al, ; Pinnell et al, ; Sharma et al, ). Accordingly Zmiz1 is expressed by several cell types in the injured cerebral cortex and its increase is also visible by immunostaining (Supporting Information Figure S9).…”

Section: Discussionmentioning

confidence: 99%

Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

Mattugini

Merl-Pham

Petrozziello

et al. 2018

Glia

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Traumatic brain injury frequently affects the cerebral cortex, yet little is known about the differential effects that occur if only the gray matter (GM) is damaged or if the injury also involves the white matter (WM). To tackle this important question and directly compare similarities and differences in reactive gliosis, we performed stab wound injury affecting GM and WM (GM+) and one restricted to the GM (GM-) in the adult murine cerebral cortex. First, we examined glial reactivity in the regions affected (WM and GM) and determined the influence of WM injury on reactive gliosis in the GM comparing the same area in the two injury paradigms. In the GM+ injury microglia proliferation is increased in the WM compared with GM, while proliferating astrocytes are more abundant in the GM than in the WM. Interestingly, WM lesion exerted a strong influence on the proliferation of the GM glial cells that was most pronounced at early stages, 3 days post lesion. While astrocyte proliferation was increased, NG2 glia proliferation was decreased in the GM+ compared with GM- lesion condition. Importantly, these differences were not observed when a lesion of the same size affected only the GM. Unbiased proteomic analyses further corroborate our findings in support of a profound difference in GM reactivity when WM is also injured and revealed MIF as a key regulator of NG2 glia proliferation.

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The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis

Cited by 29 publications

References 51 publications

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci

Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

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