TY - JOUR
T1 - Unlocking the potential
T2 - m6A-RNA methylation in severe epidermolysis bullosa simplex
AU - Balacco, Dario Leonardo
AU - Hewitt, Benjamin J.
AU - Bardhan, Ajoy
AU - Shriane, Lisa M.
AU - Hunjan, Manrup
AU - Hickerson, Robyn
AU - Heagerty, Adrian H. M.
AU - Chapple, Iain L.
N1 - Publisher Copyright:
© 2025 The Author(s).
PY - 2025/7
Y1 - 2025/7
N2 - Epidermolysis bullosa simplex (EBS) is a rare genetic disorder, resulting from mutations in keratin 5 and keratin 14 (KRT14), and is characterised by skin fragility, herpetiform blistering, and the development of confluent palmoplantar keratoderma and nail dystrophy. Inflammation, pain and itch are the most common complications of severe EBS. However, pathophysiological mechanisms remain poorly characterised at a molecular level. Recently, RNA N6-methyladenosine (m6A) nucleotide modification has been implicated in several cutaneous physiological processes, including epidermal differentiation, inflammation, adaptive immune responses, host–pathogen interactions, wound healing and tissue repair. Nevertheless, the role of m6A in EBS has yet to be defined. In this pilot study, we investigated the gene expression of key regulators of m6A, such as writers Methyltransferase-like 3 and 4 (METTL3 and METTL14), readers YTH domain-containing proteins (YTHDC1, YTHDC2, YTHDC3) and YTH domain-containing family proteins (YTHDF1 and YTHDF2) and erasers fat mass and obesity-associated (FTO) and alkB homolog 5 (ALKBH5), as well as total RNA m6A levels in the EB keratinocites cell line (KEB-7) derived from a patient with severe EBS, carrying the KRT14 R125P mutation. NEB-1 cells, derived from a healthy donor, were employed as controls. RNAseq and quantitative RT-PCR demonstrated up-regulation of the writer METTL14, while FTO was down-regulated. Moreover, the total RNA m6A colorimetric assay reported higher levels of m6A in severe EBS cells (KEB-7). Additionally, increased expression of the reader of YTHDC1 suggests a dysregulation of downstream pathways. These findings suggest a potential role for m6A in determining complications in severe EBS; however, its role and effects need to be fully elucidated.
AB - Epidermolysis bullosa simplex (EBS) is a rare genetic disorder, resulting from mutations in keratin 5 and keratin 14 (KRT14), and is characterised by skin fragility, herpetiform blistering, and the development of confluent palmoplantar keratoderma and nail dystrophy. Inflammation, pain and itch are the most common complications of severe EBS. However, pathophysiological mechanisms remain poorly characterised at a molecular level. Recently, RNA N6-methyladenosine (m6A) nucleotide modification has been implicated in several cutaneous physiological processes, including epidermal differentiation, inflammation, adaptive immune responses, host–pathogen interactions, wound healing and tissue repair. Nevertheless, the role of m6A in EBS has yet to be defined. In this pilot study, we investigated the gene expression of key regulators of m6A, such as writers Methyltransferase-like 3 and 4 (METTL3 and METTL14), readers YTH domain-containing proteins (YTHDC1, YTHDC2, YTHDC3) and YTH domain-containing family proteins (YTHDF1 and YTHDF2) and erasers fat mass and obesity-associated (FTO) and alkB homolog 5 (ALKBH5), as well as total RNA m6A levels in the EB keratinocites cell line (KEB-7) derived from a patient with severe EBS, carrying the KRT14 R125P mutation. NEB-1 cells, derived from a healthy donor, were employed as controls. RNAseq and quantitative RT-PCR demonstrated up-regulation of the writer METTL14, while FTO was down-regulated. Moreover, the total RNA m6A colorimetric assay reported higher levels of m6A in severe EBS cells (KEB-7). Additionally, increased expression of the reader of YTHDC1 suggests a dysregulation of downstream pathways. These findings suggest a potential role for m6A in determining complications in severe EBS; however, its role and effects need to be fully elucidated.
UR - https://www.scopus.com/pages/publications/105012317538
U2 - 10.1042/BSR20253141
DO - 10.1042/BSR20253141
M3 - Article
C2 - 40700032
AN - SCOPUS:105012317538
SN - 0144-8463
VL - 45
SP - 429
EP - 438
JO - Bioscience Reports
JF - Bioscience Reports
IS - 7
ER -
