Forkhead Box C1 Regulates Human Primary Keratinocyte Terminal Differentiation

Abstract

The epidermis serves as a critical protective barrier between the internal and external environment of the human body. Its remarkable barrier function is established through the keratinocyte (KC) terminal differentiation program. The transcription factors specifically regulating terminal differentiation remain largely unknown. Using a RNA-sequencing (RNA-seq) profiling approach, we found that forkhead box c 1 (FOXC1) was significantly up-regulated in human normal primary KC during the course of differentiation. This observation was validated in human normal primary KC from several different donors and human skin biopsies. Silencing FOXC1 in human normal primary KC undergoing differentiation led to significant down-regulation of late terminal differentiation genes markers including epidermal differentiation complex genes, keratinization genes, sphingolipid/ceramide metabolic process genes and epidermal specific cell-cell adhesion genes. We further demonstrated that FOXC1 works down-stream of ZNF750 and KLF4, and upstream of GRHL3. Thus, this study defines FOXC1 as a regulator specific for KC terminal differentiation and establishes its potential position in the genetic regulatory network.

CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation

“…CARD14 mRNA and CARD14 protein expression was similarly induced in cultured human keratinocytes concurrent with the keratinocyte differentiation marker involucrin ( Figure 1—figure supplement 1E and F ). The CARD14 mRNA expression data agree with published transcriptomic datasets of differentiating human keratinocytes ( Bin et al, 2016 ) and organotypic epidermis ( Lopez-Pajares et al, 2015 ; Figure 1—figure supplement 1G ).…”

“…( F ) Samples were produced as in ( E ), protein lysates were immunoblotted for CARD14, Involucrin and HSP90. ( G ) Expression of CARD14 mRNA from transcriptomes of human primary Keratinocytes (GSE73305) ( Bin et al, 2016 ) and organotypic epidermal tissue (GSE52954) ( Lopez-Pajares et al, 2015 ) at different differentiation stages. ( D, E and F ) representative from three independent experiments.…”

Transcriptional correlates of proximal-distal identify and regeneration timing in axolotl limbs

“…foxc1, a forkhead family transcription factor, was also expressed more highly in upper arm samples. Recently, foxc1 was shown to regulate the terminal differentiation of human keratinocytes (Bin et al, 2016), suggesting yet another potential epithelial difference between regenerating fore and upper limbs. Finally, tbx5 is a transcription factor that specifies the identity of fore limb cells during limb development and is enriched in axolotl fore limb blastemal tissue during regeneration (Khan et al, 2002).…”

The Role of KLF4 in Alzheimer’s Disease

“…During the embryonic development, KLF 4 was higher expressed in the late stage of embryonic development. While in mature tissues and organs, KLF 4 is mainly expressed in the gastrointestinal tract, oral cavity, skin epidermis, vascular endothelium and kidney, and is less expressed in the brain ( Segre et al, 1999 ; Ghaleb et al, 2011 ; Liu et al, 2013 ; Chen et al, 2015 ; He et al, 2015 ; Bin et al, 2016 ). It is thought to play significant role in regulating cell proliferation and differentiation.…”