Mettl3-catalyzed mA regulates histone modifier and modification expression in self-renewing somatic tissue.

-methyladenosine (mA) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of mA in a self-renewing somatic tissue, we deleted in epidermal progenitors in vivo. Mice lacking demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations.

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.

Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2-knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis.

Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist.

Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling.

Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibility to malignant transformation, independent of melanin and ultraviolet exposure. These differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from darkly pigmented skin.

Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma.

Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum.

Loss of TET2 Tips the Scales Toward Tumorigenesis.

DNA methylation and demethylation function in the balance between cellular differentiation and cancer. Although the roles of DNA methyltransferases have been extensively explored in epidermal biology, ten-eleven translocation (TET) demethylase enzymes are poorly understood. In their new article in the Journal of Investigative Dermatology, Boudra et al.

MLL4 mediates differentiation and tumor suppression through ferroptosis.

The epigenetic regulator, (), has been described as an essential gene in both humans and mice. In addition, it is one of the most commonly mutated genes in all of cancer biology. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression.

Methyltransferases in the Pathogenesis of Keratinocyte Cancers.

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes.

The METTL3-mA Epitranscriptome: Dynamic Regulator of Epithelial Development, Differentiation, and Cancer.

Dynamic modifications on RNA, frequently termed both, "RNA epigenetics" and "epitranscriptomics", offer one of the most exciting emerging areas of gene regulation and biomedicine. Similar to chromatin-based epigenetic mechanisms, writers, readers, and erasers regulate both the presence and interpretation of these modifications, thereby adding further nuance to the control of gene expression. In particular, the most abundant modification on mRNAs, N-methyladenosine (mA), catalyzed by methyltransferase-like 3 (METTL3) has been shown to play a critical role in self-renewing somatic epithelia, fine-tuning the balance between development, differentiation, and cancer, particularly in the case of squamous cell carcinomas (SCCs), which in aggregate, outnumber all other human cancers.

Lgr6 marks epidermal stem cells with a nerve-dependent role in wound re-epithelialization.

Stem cells support lifelong maintenance of adult organs, but their specific roles during injury are poorly understood. Here we demonstrate that Lgr6 marks a regionally restricted population of epidermal stem cells that interact with nerves and specialize in wound re-epithelialization. Diphtheria toxin-mediated ablation of Lgr6 stem cells delays wound healing, and skin denervation phenocopies this effect.

From Enhancers to Keratinocyte Cancers.

Epigenetic dysregulation and disruption of gene enhancer networks are both pervasive in human cancers, and yet, their roles in keratinocyte cancers are poorly understood. Utilizing patient samples, Yao et al. (2020) provide an initial framework for understanding the underlying mechanisms by integrating enhancer and transcriptional alterations that occur during the progression of basal cell and squamous cell carcinomas.

Epigenetic and metabolic interplay in cutaneous squamous cell carcinoma.

With the ageing of the population and increased levels of recreational sun exposure and immunosuppression, cutaneous squamous cell carcinoma (cSCC), is both an enormous and expanding clinical and economic issue. Despite advances in therapy, up to 5000-8000 people are estimated to die every year from cSCC in the U.S.

The endangered physician-scientist and COVID-19.

The COVID-19 pandemic has affected almost every stakeholder in healthcare, including the vulnerable population of clinician investigators known as physician-scientists. In this commentary, Rao et al. highlight the underappreciated challenges and opportunities, and present solutions, for physician-scientists vis-à-vis the uniquely disruptive event of the pandemic.

Whole-Exome and Transcriptome Analysis of UV-Exposed Epidermis and Carcinoma In Situ Reveals Early Drivers of Carcinogenesis.

Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma. Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser captured microdissection of human SCCIS and the adjacent epidermis to isolate genomic DNA and RNA for next-generation sequencing.

Loss of Methylation Modification Marks the Presence of Psoriasis.

The reversibility of epigenetic alterations makes them the attractive targets for therapeutic discovery; however, their potential remains untapped owing to a lack of mechanistic understanding, particularly for inflammatory skin disorders. Here, Li and colleagues begin to fill these gaps by identifying the loss of the DNA hydroxymethylation mark 5-hmC in psoriasis and presenting compelling evidence for its potential contribution to disease manifestations.

LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma?

Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most frequent cancer; it can be locally invasive and metastatic. cSCC is an immense clinical and economic problem given its sheer incidence and potential morbidity and mortality, particularly in the elderly and immunocompromised. Epigenetics has emerged as one of the most exciting areas of human biology, impacting virtually all areas of cellular physiology.

Pharmacologic Activation of the G Protein-Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma.

Background & Aims: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors.

FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.

Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target.

LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors.

Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown.

The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease.

Epigenetic regulation is critical for the precise control of cellular fate and developmental programs. Disruption of epigenetic information is increasingly appreciated as a potential driving mechanism in both developmental disorders as well as ubiquitous diseases such as cancer. Consistent with this, mutations in histone modifying enzymes are amongst the most frequent events in all of human cancer.

Paget's Diseases: United by Epidermis and Epigenetics.

Almost 150 years have passed since Sir James Paget described the disease that bears his name, but the molecular etiology and cellular origins of Paget's disease remain poorly understood. Herein, Zhang et al. (2018) bring Paget's disease into the genomics era, providing evidence for an epidermal origin for Paget's disease, as well as a high incidence of mutations in genes encoding epigenetic regulators.

KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis.

Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator () is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification.