Deciphering the Epigenetic Code of Stem Cells Derived From Dental Tissues

Stem cells derived from dental tissues (DSCs) exhibit multipotent regenerative potential in pioneering tissue engineering regimens. The multipotency of DSCs is critically regulated by an intricate range of factors, of which the epigenetic influence is considered vital. To gain a better understanding of how epigenetic alterations are involved in the DSC fate determination, the present review overviews the current knowledge relating to DSC epigenetic modifications, paying special attention to the landscape of epigenetic modifying agents as well as the related signaling pathways in DSC regulation. In addition, insights into the future opportunities of epigenetic targeted therapies mediated by DSCs are discussed to hold promise for the novel therapeutic interventions in future translational medicine.

HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins

HAUSP (herpes virus-associated ubiquitin-specific protease), also known as Ubiquitin Specific Protease 7, plays critical roles in cellular processes, such as chromatin biology and epigenetics, through the regulation of different signaling pathways. HAUSP is a main partner of the “Epigenetic Code Replication Machinery,” ECREM, a large protein complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING), finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60. Due to its deubiquitinase activity and its ability to team up through direct interactions with several epigenetic regulators, mainly UHRF1, DNMT1, TIP60, the histone lysine methyltransferase EZH2, and the lysine-specific histone demethylase LSD1, HAUSP positions itself at the top of the regulatory hierarchies involved in epigenetic silencing of tumor suppressor genes in cancer. This review highlights the increasing role of HAUSP as an epigenetic master regulator that governs a set of epigenetic players involved in both the maintenance of DNA methylation and histone post-translational modifications.

Vincent Cristofalo “Rising Star”Award: DNA Methylation Landscapes in Aging

The epigenetic code can be thought of as the operating system of the cell. It controls the most basic and critical cellular processes including differentiation, replication, metabolism, and signaling. Yet, with age, the epigenetic landscape is remodeled, bringing about widespread consequences for cellular and tissue identity, integrity, and functioning. But, what if like computer programmers, we could discover how to recode or restore the original program? The revolutionary discoveries by Yamanaka and Takahashi suggests this may be possible. While early experiments showed that Yamanaka factors could be used to convert somatic cells into induced pluripotent stem cells, more recent work by us and others have shown that signatures of epigenetic aging are also wiped clean during this process. What’s more, epigenetic age reversal appears to take place early in the process and thus can be achieved without the cell _needing to dedifferentiate. Building off of this discovery, our lab is combining novel experiments and advanced bioinformatic techniques to decipher the epigenetic code and determine how it is remodeled during aging, development, and reprogramming. In our recent work, we have made advancements in mapping the epigenetic alterations observed in aging and linking them to both cellular processes and disease etiology. We have identified specific age changes in mouse and human cells that reflect mitotic history, cellular senescence, oxidative damage, and mitochondrial dysfunction. We have also demonstrated that these changes inform differences in organismal lifespan and/or disease etiology at the tissue level. Overall, this work has sweeping implications for our basic understanding of epigenetic aging and reprogramming, and will help provide the foundation for potent therapeutics that extend healthspan and lifespan.

Possible Hypothetical Mode of Action of ECT (Electroconvulsive Therapy) Based on DNA Dipole Character and Epigenetics

The human genome consists of roughly 23000 genes which cannot explain the enormous diversity of proteins or behavior. A second epigenetic code warrants adaptive variation of gene expression. The rationale of this variation are transfer reactions such as methylation, acetylation or phosphorylation of DNA or histones including reverse reactions which are supposed to be altered by electroconvulsive therapy (ECT). The method has been successfully used since the 1930ies but the underlying molecular mechanism of action has not been elucidated yet. The paper discusses the theoretical involvement of epigenetic gene expression as an adaptive process to explain biochemical changes after ECT administration.

Accurate prediction of functional states of cis-regulatory modules reveals the universal epigenetic code in mammals

Predicting cis-regulatory modules(CRMs) in a genome and predicting their functional states in various cell/tissue types of the organism are two related challenging computational tasks. Most current methods attempt to achieve both simultaneously using epigenetic data. Though conceptually attractive, they suffer high false discovery rates and limited applications. To fill the gaps, we proposed a two-step strategy to first predict a map of CRMs in the genome, and then predict functional states of the CRMs in various cell/tissue types of the organism. We have recently developed an algorithm for accurately predicting CRMs in a genome by integrating numerous transcription factor ChIP-seq datasets. Here, we showed that only three or four epigenetic marks data in a cell/tissue type were sufficient for a machine-learning model to accurately predict functional states of all CRMs. Our predictions are substantially more accurate than the best achieved so far. Interestingly, a model trained on different cell/tissue types in a mammal can accurately predict functional states of CRMs in different cell/tissue types of the mammal as well as in various cell/tissue types of a different mammal. Therefore, epigenetic code that defines functional states of CRMs in various cell/tissue types is universal at least in mammals. Moreover, we found that from tens to hundreds of thousands of CRMs were active in a human and mouse cell/tissue type, and up to 99.98% of them were reutilized in different cell/tissue types, while as small as 0.02% of them were unique to a cell/tissue type that might define the cell/tissue type.

There and Back Again: Hox Clusters Use Both DNA Strands

Bilaterian animals operate the clusters of Hox genes through a rich repertoire of diverse mechanisms. In this review, we will summarize and analyze the accumulated data concerning long non-coding RNAs (lncRNAs) that are transcribed from sense (coding) DNA strands of Hox clusters. It was shown that antisense regulatory RNAs control the work of Hox genes in cis and trans, participate in the establishment and maintenance of the epigenetic code of Hox loci, and can even serve as a source of regulatory peptides that switch cellular energetic metabolism. Moreover, these molecules can be considered as a force that consolidates the cluster into a single whole. We will discuss the examples of antisense transcription of Hox genes in well-studied systems (cell cultures, morphogenesis of vertebrates) and bear upon some interesting examples of antisense Hox RNAs in non-model Protostomia.

Chromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver

We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration.

Using CRISPR to understand and manipulate gene regulation

ABSTRACT Understanding how genes are expressed in the correct cell types and at the correct level is a key goal of developmental biology research. Gene regulation has traditionally been approached largely through observational methods, whereas perturbational approaches have lacked precision. CRISPR-Cas9 has begun to transform the study of gene regulation, allowing for precise manipulation of genomic sequences, epigenetic functionalization and gene expression. CRISPR-Cas9 technology has already led to the discovery of new paradigms in gene regulation and, as new CRISPR-based tools and methods continue to be developed, promises to transform our knowledge of the gene regulatory code and our ability to manipulate cell fate. Here, we discuss the current and future application of the emerging CRISPR toolbox toward predicting gene regulatory network behavior, improving stem cell disease modeling, dissecting the epigenetic code, reprogramming cell fate and treating diseases of gene dysregulation.