Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood

Runne, Heike; Kuhn, Aléxandre; Wild, Edward J.; Pratyaksha, Wirahpati; Kristiansen, Mark; Isaacs, Jeremy D.; Régulier, Etienne; Delorenzi, Mauro; Tabrizi, Sarah J.; Lüthi-Carter, Ruth

doi:10.1073/pnas.0703652104

Cited by 119 publications

(106 citation statements)

References 27 publications

(30 reference statements)

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“…Blood is a complex tissue for studying gene expression with multiple cell types and differentiation stages contributing to whole blood RNA. In previous blood gene expression studies22, 23, 24, 25 ACTB and GAPDH turnt out to be suitable reference genes. Following normalization with ACTB and GAPDH , the mRNA levels of all studied TS genes in the control group varied within the normal range.…”

Section: Methodsmentioning

confidence: 99%

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Böck

Appenzeller

Haertle

et al. 2018

Intl Journal of Cancer

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To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2‐mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age‐matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1, which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1, which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1, consistent with a disease‐causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.

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Section: Methodsmentioning

confidence: 99%

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Böck

Appenzeller

Haertle

et al. 2018

Intl Journal of Cancer

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show abstract

“…Second, lurking bias is a key threat to all biomarker studies (14,40), and a panel of 12 RNA biomarkers for HD highlighted in a previous small study (7) was not replicated (8). We have attempted to minimize bias by adhering to rigorous proposed "rules of evidence" in study design, conduct, and interpretation (40).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional modulator H2A histone family, member Y ( H2AFY ) marks Huntington disease activity in man and mouse

Chopra

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.

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“…Data are presented for the following inventoried assays: ADORA2a (Rn00583935_m1), proenkephalin 1 (PENK1) (Rn00567566_m1), regulator of G-protein signaling 4 (RGS4) (Rn00568067_m1), neurogranin (NRGN) (Rn00480741_m1), Purkinjecell protein 4 (PCP4) (Rn00564515_m1), visinin-like 1 (VSNL1) (Rn00562148_m1), and nuclear transcription factor Y gamma subunit (NFYC) (Rn00563487_m1). Expression values were calculated as described in the study by Runne et al (2007), using ␤-actin (assay ID Rn00667869_m1) as the normalization control. Similar results were obtained after normalization to 18S ribosomal RNA (assay ID 4342379-18srRNA).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

Runne¹,

Régulier²,

Kuhn³

et al. 2008

J. Neurosci.

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Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood

Cited by 119 publications

References 27 publications

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Transcriptional modulator H2A histone family, member Y ( H2AFY ) marks Huntington disease activity in man and mouse

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

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