Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults ...are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions.
Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation ...signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK−) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK− ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.
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•ALK+ and ALK− ALCL show highly similar genome-wide DNA methylation•ALCL tumor cells closely resemble undifferentiated thymic progenitor cells•Differentially methylated genes are implicated in major T cell functions•Oncogenic transcription factors produce epigenetic footprints
Using genome-wide DNA methylation profiling, Hassler et al. find that DNA methylation patterns in ALCL are related to specific thymic stages in T cell development, suggesting a thymic progenitor cell of origin. Moreover, comparison of ALK+ ALCL to ALK− ALCL indicates no ALK-specific impact on DNA methylation.
The Role of DNA Methylation in Cancer Lakshminarasimhan, Ranjani; Liang, Gangning
Advances in Experimental Medicine and Biology,
01/2016, Letnik:
945
Journal Article, Book Chapter
Recenzirano
Odprti dostop
The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale multinational consortium studies, it has ...become possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. From these genome-wide studies, it became clear that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription, but its broader consequences include maintaining the integrity of the genome and modulating immune response. Here, we describe the aberrant DNA methylation changes that take place in cancer and how they contribute to the disease phenotype. Further, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets.
Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between ...the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1-driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1-exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53-dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function.
Abstract The chromatin remodeler AT-Rich Interactive Domain 1A (ARID1A) is frequently mutated in ovarian clear cell carcinoma (OCCC) and endometriosis precursor lesions. Here, we show that knocking ...down ARID1A in an immortalized endometriosis cell line is sufficient to induce phenotypic changes indicative of neoplastic transformation as evidenced by higher efficiency of anchorage-independent growth, increased propensity to adhere to collagen, and greater capacity to invade basement membrane extract in vitro . ARID1A knockdown is associated with expression dysregulation of 99 target genes, and many of these expression changes are also observed in primary OCCC tissues. Further, pathway analysis indicates these genes fall within networks highly relevant to tumorigenesis including integrin and paxillin pathways. We demonstrate that the down-regulation of ARID1A does not markedly alter global chromatin accessibility or DNA methylation but unexpectedly, we find strong increases in the active H3K27ac mark in promoter regions and decreases of H3K27ac at potential enhancers. Taken together, these data provide evidence that ARID1A mutation can be an early stage event in the oncogenic transformation of endometriosis cells giving rise to OCCC.
Highly tumorigenic, drug‐resistant cancer stem‐like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an ...epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem‐like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem‐like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem‐like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug‐resistant phenotype.
What's new?
Cancer cells can cycle in and out of an aggressive cancer stem cell‐like state but mechanisms controlling this process are unknown. Here the authors find that these transitions occur at least in part via epigenetic alterations that drive an aggressive, drug‐resistant phenotype. These findings underscore cancer cells' capacity for rapid, adaptive phenotypic shifts that do not require driver mutations and may offer new therapeutic opportunities in the future.
Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of ...aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland.
Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages.
Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.
The complex interplay between epigenetic mechanisms such as DNA methylation, histone modification, and nucleosome positioning regulate gene expression potential and chromatin organization over cell ...generations. Mutations in mediators of epigenetic processes can contribute to considerable alterations of gene expression and disrupt cellular identity and function, resulting in the development of malignancies. Large-scale sequencing efforts have uncovered germline and somatic mutations in many epigenetic modulators including DNA methyltransferases, histone tail modifiers, and subunits of chromatin remodeling complexes. Specifically, the components of the SWI/SNF remodeling complexes are mutated in upwards of 20% of all tumors. However, our understanding of the molecular changes that take place due to these mutations is still incomplete. This dissertation aims to examine the role of SWI/SNF complex proteins in shaping the epigenetic landscape of cancer and how the interplay between the various epigenetic mechanisms contribute to functional alterations. First, I demonstrated that induction of SNF5 in malignant rhabdoid tumor (MRT) cell line TCC642 significantly altered the transcriptome and restores aberrant expression of several genes closer to normal levels. Further, I surveyed the epigenome using the DNA methylation array-based AcceSssIble assay and uncovered several potential direct epigenetic targets of SNF5. Finally, I established TRIM2 as a downstream target of SNF5. Thus, I found that re-expression of SNF5 in TCC642 cells regulated target gene expression in part by remodeling chromatin. Next, using an endometriosis cell line model, I comprehensively characterized gene expression, histone modification, chromatin accessibility, and DNA methylation changes that take place due to loss of ARID1A. Specifically, I showed that the loss of ARID1A triggered a considerable re-distribution of the H3K27ac histone modification and affected the expression of a number of genes critical to ovarian cancer development. These molecular aberrations contributed to phenotypic changes including increased anchorage-independent colony formation and increased invasion of basement membrane extract in vitro. Thus, this dissertation sheds light on how mutations in a single component of an epigenetic complex can not only alter the epigenome but can also promote functional changes and possibly contribute to oncogenesis.
Hematopoietic stem cells (HSCs) are a rare population of self-renewing bone marrow (BM) cells that give rise to all lineages of mature blood cells including those comprising the immune system. While ...many regulatory factors controlling HSC differentiation and blood production have been identified, the role of inflammatory cytokines in this process is still largely unknown. Interleukin-1 (IL-1) is a prototypical inflammatory cytokine with critical functions in innate immune responses. While IL-1 is associated with increased myeloid cell production, whether it regulates myeloid lineage specification from HSCs remains unclear. Here, we use cutting-edge approaches to directly interrogate the role of IL-1 in regulating HSC differentiation during steady state and in response to hematopoietic stress. Using continuous single-cell tracking technology, we find that IL-1 accelerates HSC growth and instructs HSC differentiation along the granulocyte–macrophage (GM) lineage in vitro. Strikingly, these effects are accompanied by the rapid activation of a gene program driven by the transcription factor Pu.1, the master regulator of GM lineage commitment, as shown by qRT-PCR analyses and lineage tracking in Pu.1-eYFP reporter mice. Consistent with these in vitro observations, the pool of HSC-derived progenitor cells giving rise to the GM lineage is significantly reduced in size in IL-1 receptor (Il1r1)-deficient mice and Il1r1-deficient mice show significantly impaired recovery of GM-lineage output following 5-FU-mediated myeloablation. We are now working at identifying the cellular components of the BM microenvironment that produce IL-1 in these conditions. Collectively, our results identify IL-1 as a key regulator of myeloid cell production from HSCs and provide compelling evidence for a direct role of inflammatory cytokines in shaping the immune system. They advance our understanding of how blood cell production is regulated in both steady state and stress conditions, which could have important implications for the treatment of acute inflammation and autoimmune diseases.
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