Dry Eye Disease (DED) is prevalent, affecting almost 7% of the US adult population. Untreated DED can lead to inflammation of the eye, corneal abrasions and ulcers, and vision loss [1], [2]. The most common type of DED, known as evaporative DED (EDED), is associated with decreased production of meibum, an oily film that covers the eye surface and prevents tear film evaporation [3], [4]. Decreased meibum production results from dysfunction of the Meibomian glands (MGs) [1]; these are specialized sebaceous glands located in the tarsal plate of the upper and lower eyelids whose major function is to secrete meibum [3], [4]. MG shrinkage or dropout, accompanied by reduced quantity and quality of meibum, is increased in aging; in line with this, EDED incidence is highest in aging populations [5], [6]. Available treatments, including lipid-containing eye drops, warm compresses to improve meibum flow, and anti-inflammatory drugs, provide limited and temporary efficacy for EDED, and the disease currently has no cure [7]. Improved understanding of the cellular and molecular processes underlying MG homeostasis will be crucial in developing more effective therapeutics for this common condition that negatively affects quality of life.

Each MG consists of a central duct and multiple connecting acini, in which basal stem cells constantly proliferate toward the center of acinus to produce meibocytes that undergo sequential differentiation to accumulate lipid content for meibum synthesis [8], [9]. Failed MG stem cell activity is proposed as an underlying cause of MG dropout [10], [11], but the mechanisms that govern the proliferation, survival, and differentiation of MG stem cells are poorly understood.

Chromatin regulators play key roles in governing stem cell proliferation, differentiation, and maintenance in epithelial tissues, and are druggable targets with therapeutic potential. Among them, histone deacetylases (HDACs) remove histone acetyl groups, resulting in compaction of chromatin and transcriptional repression [12], [13]. HDACs can also deacetylate key transcription factors, such as p53 and c-MYC, regulating their stability and activity [14], [15].

The Class I HDACs, HDAC1, HDAC2, and HDAC3, have strong deacetylase activity towards histones and are associated with at least four major repressive complexes, indicating that they have isoform and context-dependent effects. HDAC1 and HDAC2 are closely related, function redundantly, or semi-redundantly, in some contexts [16], [17], and associate with the nucleosome remodeling and deacetylase complex (NuRD) [18], [19], the transcriptional regulatory protein Sin3A [20], corepressor of REST (CoREST) complex [21], and the mitotic deacetylase complex (MiDAC) [22]. By contrast, HDAC3 uniquely associates with the SMRT/N-CoR corepressor complex [23], suggesting that it regulates a set of target genes distinct from that controlled by HDAC1/2. In line with this, HDAC1/2 are required for proliferation and survival of epidermal basal cells [24], [25], while HDAC3 plays essential roles in preventing premature epidermal differentiation [26].

HDAC inhibitors have been developed and approved for the treatment of cancers such as cutaneous and peripheral T-cell lymphoma, as well as multiple myeloma [27], [28]. HDAC inhibitors can also have anti-inflammatory effects [29], [30]. As DED is an inflammatory ocular disease [31], [32], HDAC inhibitors have been suggested as an alternative therapeutic approach for DED. This notion gains support from a study showing that controlled release of an HDAC inhibitor into the lacrimal gland can effectively mitigate inflammation in DED-afflicted mice [33]. However, currently available HDAC inhibitors generally act broadly on multiple HDAC family members and can have severe side effects [34], [35]. Designing more specific therapeutics will require improved knowledge of the functions of individual HDACs in MG homeostasis. While constitutive deletion of Hdac1 and Hdac2 in developing MG of K14-Cre Hdac1fl/flHdac2fl/+ mice causes MG hyperplasia [36], the functions of Hdac1 and Hdac2 in adult MG epithelium have not been examined, and any roles played by Hdac3 in this tissue are unknown. To investigate the overlapping and unique functions of HDAC1/2 and HDAC3 in MG homeostasis we examined the phenotypic and molecular consequences of inducible deletion of these genes in adult MG epithelium.