Gradient of E2A Activity in B-Cell Development

ABSTRACT The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). E2A encodes two products, E12 and E47, that are part of the basic helix-loop-helix (bHLH) family of transcription factors and are central in B lineage differentiation. E2A haplo-insufficiency hinders progression through three major checkpoints in B-cell development: commitment into the B lineage, at the pro-B to pre-B transition, and in the induction of immunoglobulin M (IgM) expression required for a functional BCR. These observations underscore the importance of E2A gene dosage in B-cell development. Here we show that a higher proportion of pro-B cells in E2A+/− mice is in the cell cycle compared to that in wild-type littermates. This increase correlates with lower p21waf/cip1 levels, indicating that E2A has an antiproliferative function in B-cell progenitors. Ectopic expression in the B lineage of SCL/Tal1, a tissue-specific bHLH factor that inhibits E2A function, blocks commitment into the B lineage without affecting progression through later stages of differentiation. Furthermore, ectopic SCL expression exacerbates E2A haplo-insufficiency in B-cell differentiation, indicating that SCL genetically interacts with E2A. Taken together, these observations provide evidence for a gradient of E2A activity that increases from the pre-pro-B to the pre-B stage and suggest a model in which low levels of E2A (as in pro-B cells) are sufficient to control cell growth, while high levels (in pre-B cells) are required for cell differentiation. The antiproliferative function of E2A further suggests that in B-ALL associated with t(1;19) and t(17;19), the disruption of one E2A allele contributes to leukemogenesis, in addition to other anomalies induced by E2A fusion proteins.

Download Full-text

Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

Blood ◽

10.1182/blood-2014-12-575688 ◽

2015 ◽

Vol 126 (2) ◽

pp. 144-152 ◽

Cited By ~ 73

Author(s):

Rajesh Somasundaram ◽

Mahadesh A. J. Prasad ◽

Jonas Ungerbäck ◽

Mikael Sigvardsson

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Cell Development ◽

B Cell Development ◽

Human Leukemia ◽

Acute Leukemias ◽

B Lineage

Abstract B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cells display a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of genetic changes in leukemia has revealed that several key regulators of normal B-cell development, including IKZF1, TCF3, EBF1, and PAX5, are genetically altered in a large portion of the human B-lineage acute leukemias. This opens the possibility of directly linking the disrupted development as well as aberrant gene expression patterns in leukemic cells to molecular functions of defined transcription factors in normal cell differentiation. This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.

Download Full-text

Regulation of Homeostatic and Malignant B Cell Development By the Tetraspanin CD53

Blood ◽

10.1182/blood-2018-99-111957 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3699-3699

Author(s):

Zev J. Greenberg ◽

Darlene A. Monlish ◽

Rachel L. Bartnett ◽

Laura G. Schuettpelz

Keyword(s):

B Cells ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Mapk Signaling ◽

Cell Development ◽

B Cell Development ◽

Malignant Cells ◽

Hematopoietic Stem ◽

Cell Counts ◽

B Lineage

Abstract Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy, most commonly originating from the transformation of progenitor cells of the B cell lineage (B cell precursor-ALL; BCP-ALL). Treatment of patients with high-risk or relapsed disease is difficult and prognosis remains poor in pediatric patients, with an even worse survival rate for adult BCP-ALL. Previous studies have shown an association of enhanced CD53 expression with many B cell malignancies, suggesting upregulation of CD53 may be implicated in carcinogenesis or maintenance of malignant cells. CD53 is a member of the tetraspanin family of transmembrane proteins, classically involved in cell adhesion, proliferation, and survival, and expressed exclusively on hematopoietic cells. While several studies have implicated a role for CD53 in regulating mature B cell proliferation, its role in early B cell development is not yet known. To elucidate the contribution of CD53 to normal and malignant B cell development, we have generated a CD53 knockout mouse. In our CD53-/- mouse, we observe no differences in total white blood cell counts, yet the fraction of peripheral blood B cells is significantly reduced by 31% compared to wild-type (WT) controls (28.3% vs. 19.5%; p<0.005). During homeostatic B lymphopoiesis, CD53 increases through development, beginning at the pre-pro-B cell stage and reaching highest expression on mature B cells. Further investigation into the loss of B cells revealed that immature pre-B cells in the bone marrow and mature B cells in the spleen and lymph nodes are significantly diminished upon loss of CD53, resulting from increased apoptosis in CD53-/- mice. B cell differentiation of CD53-/- hematopoietic stem cells (HSCs) in vitro corroborates the dependence on CD53 for normal differentiation, as CD53-/- cultures have 26% fewer B cells than controls (p=0.033). Investigation into the signaling differences between WT and CD53-/- B cell progenitors by mass cytometry (CyTOF) suggests that decreased PI3K/Akt and MAPK signaling could be driving this loss. With the observed loss of both B cell progenitors and mature B cells in CD53-deficient mice, CD53-/- mice were recently crossed to Eμ-Myc transgenic mice, a model of B-lineage leukemia/lymphoma, to generate WT, CD53-/-, Eμ-Myc+;CD53+/+, and Eμ-Myc+;CD53-/- groups to assess whether loss of CD53 alters the pathology or survival of these mice. As observed in human patients, moribund Eμ-Myc+ mice significantly upregulate CD53 on malignant cells, suggesting a potential role for CD53 during pathogenesis. Ongoing experiments are aimed at elucidating the mechanism by which CD53 promotes homeostatic B cell development and determining the potential of CD53 as a therapeutic target for B lineage malignancies. Disclosures No relevant conflicts of interest to declare.

Download Full-text

B Cell Lineage-Specific Deletion of Icsbp/IRF8 Reveals Roles for IRF8 in the Regulation of Marginal Zone and Follicular B Cell Development.

Blood ◽

10.1182/blood.v110.11.1334.1334 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1334-1334

Author(s):

Hongsheng Wang ◽

Jianxun Feng ◽

Chang Hoon Lee ◽

Herbert Morse

Keyword(s):

B Cells ◽

B Cell ◽

Marginal Zone ◽

Cell Development ◽

B Cell Development ◽

Conditional Knockout ◽

Myelogenous Leukemia ◽

Exon 2 ◽

B Lineage ◽

B Lineage Cells

Abstract Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor that expresses in T cells, B cells and macrophages and plays a role in myeloid development. Targeted deletion of IRF8 in mice (IRF8−/−) induced progressive increase in the numbers of granulocytes in various lymphoid organs and development of a syndrome similar to human chronic myelogenous leukemia. In addition to defective development of macrophages and dendritic cells, B cell development was also impaired in IRF8−/− mice. This includes decreased numbers of early B cells, expanded marginal zone (MZ) B cells and diminished follicular (OF) B2 cells. Because abnormal myeloid cells could alter microenvironment required for normal B cell development, we have generated IRF8 conditional knockout mice to specifically investigate the function of IRF8 in B lineage cells. Mice were engineered to have exon 2, encoding the DNA binding domain of IRF8, flanked by loxP sites (designated IRF8f/+). These mice were then crossed with the CD19Cre strain in which the expression of Cre-recombinase is controlled by the endogenous CD19 locus. Homozygous mice (designated (IRF8f/f x Cre)F1) underwent germline excision of IRF8 in CD19+ B lineage cells. As a result, there was no detectable mRNA and protein of IRF8 in their splenic B cells. Flow cytometry analysis revealed expanded MZ B cells and reduced OF B2 cells in the spleen of (IRF8f/f x Cre)F1 mice. Interestingly, the expression level of CD23 on OF B cells was significantly decreased in (IRF8f/f x Cre)F1 mice, indicating that IRF8 is required for maintaining a normal OF phenotype. In the peritoneum of (IRF8f/f x Cre)F1 mice, while the numbers of B1a and B2 cells were slightly decreased, the number of B1b cells was slightly increased. Furthermore, BXH2 mice carrying a mutation (C915T) in the Icsbp1 gene exhibited similar expansion of MZ B cells and low expression of CD23 in OF B cells. Taken together, these analyses indicate that IRF8 is required for development of normal MZ and B2 cells.

Download Full-text

Precursor B Cell Acute Lymphoblastic Leukemia Induces Pro-Leukemic Changes in the Bone Marrow Microenvironment That Contribute to Therapeutic Resistance

Blood ◽

10.1182/blood.v120.21.1466.1466 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1466-1466

Author(s):

Christopher D Chien ◽

Elizabeth D Hicks ◽

Paul P Su ◽

Haiying Qin ◽

Terry J Fry

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cells ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Cell Development ◽

B Cell Development ◽

Bone Marrow Microenvironment ◽

Therapeutic Resistance

Abstract Abstract 1466 Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although cure rates for this disease are approximately 90%, ALL remains one of the leading causes cancer-related deaths in children. Thus, new treatments are needed for those patients that do not respond to or recur following standard chemotherapy. Understanding the mechanisms underlying resistance of pediatric ALL to therapy offers one approach to improving outcomes. Recent studies have demonstrated the importance of communication between cancer cells and their microenvironment and how this contributes to the progression and therapeutic resistance but this has not been well studied in the context of ALL. Since the bone marrow is presumed to be the site of initiation of B precursor ALL we set out in our study to determine how ALL cells utilize the bone marrow milieu in a syngeneic transplantable model of preB cell ALL in immunocompetent mice. In this model, intravenously injected preB ALL develops first in the bone marrow, followed by infiltration into the spleen, lymph node, and liver. Using flow cytometry to detect the CD45.2 isoform following injection into B6CD45.1+ congenic recipients, leukemic cells can be identified in the bone marrow as early as 5 days after IV injection with a sensitivity of 0.01%-0.1%. The pre-B ALL line is B220+/CD19+/CD43+/BP1+/IL-7Ralpha (CD127)+/CD25-/Surface IgM-/cytoplasmic IgM+ consistent with a pre-pro B cell phenotype. We find that increasing amounts of leukemic infiltration in the bone marrow leads to an accumulation of non-malignant developing B cells at stages immediately prior to the pre-pro B cell (CD43+BP1-CD25-) and a reduction in non-malignant developing pre B cells at the developmental stage just after to the pre-pro B cell stage (CD43+BP1+CD25+). These data potentially suggest occupancy of normal B cell developmental niches by leukemia resulting in block in normal B cell development. Further supporting this hypothesis, we find significant reduction in early progression of ALL in aged (10–12 month old) mice known to have a deficiency in B cell developmental niches. We next explored whether specific factors that support normal B cell development can contribute to progression of precursor B cell leukemia. The normal B cell niche has only recently been characterized and the specific contribution of this niche to early ALL progression has not been extensively studied. Using a candidate approach, we examined the role of specific cytokines such as Interleukin-7 (IL-7) and thymic stromal lymphopoietin (TSLP) in early ALL progression. Our preB ALL line expresses high levels of IL-7Ralpha and low but detectable levels of TLSPR. In the presence of IL-7 (0.1 ng/ml) and TSLP (50 ng/ml) phosphSTAT5 is detectable indicating that these receptors are functional but that supraphysiologic levels of TSLP are required. Consistent with the importance of IL-7 in leukemia progression, preliminary data demonstrates reduced lethality of pr-B cell ALL in IL-7 deficient mice. Overexpression of TSLP receptor (TSLPR) has been associated with high rates of relapse and poor overall survival in precursor B cell ALL. We are currently generating a TSLPR overepressing preBALL line to determine the effect on early ALL progression and are using GFP-expressing preB ALL cells to identify the initial location of preB ALL occupancy in the bone marrow. In conclusion, or model of early ALL progression provides insight into the role of the bone marrow microenvironment in early ALL progression and provides an opportunity to examine how these microenvironmental factors contribute to therapeutic resistance. Given recent advances in immunotherapy for hematologic malignancies, the ability to study this in an immunocompetent host will be critical. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Bcl6 RD2 Domain Is Essential For Pre-Germinal Center B Cell Development

Blood ◽

10.1182/blood.v122.21.783.783 ◽

2013 ◽

Vol 122 (21) ◽

pp. 783-783

Author(s):

Chuanxin Huang ◽

Ann Haberman ◽

Ari M. Melnick

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Transcriptional Repression ◽

Cell Development ◽

B Cell Development ◽

Wild Type ◽

Btb Domain ◽

Repression Domain

Abstract The transcriptional repressor Bcl6 is a master regulator of the germinal center (GC) reaction through directing naïve B cells and CD4+ T cells to differentiate into GC B cells and follicular T helper (TFH) cells respectively. Bcl6 mediates its action largely by recruitment of co-repressors through its N-terminal BTB domain and its middle second repression domain (RD2). The BTB domain repression function is critical for GC B cell survival and proliferation, but not important for TFH cell differentiation. However, the in vivobiological function of RD2 remains unknown. To explore the specific role of RD2 transcriptional repression in the GC reaction, we generated a knockin mouse model in which the endogenous Bcl6 locus encodes a mutant form of the protein that specifically disrupts RD2 mediated transcriptional repression. RD2 mutant mice were developmentally indistinguishable from wild-type mice and displayed normal B cell development prior to the GC phase. However, these mice failed to accumulate GCs after immunization with sheep blood cells and exhibited remarkably impaired production of high-affinity antibodies 21 days after T-cell dependent antigen immunization, indicative of severe deficiency of the GC reaction. Mixed bone marrow transplantation experiments showed that RD2 loss of function led to complete loss of GC B cells and partial impairment of TFH cell differentiation in cell-intrinsic manner. Intravital imaging analysis indicated that RD2-deficent antigen-engaged B cells migrate normally to the inter-follicular zone of lymph nodes and interacted normally with cognate T helper cells. To further understand the nature of the functional defect of RD2 mutant B-cells, hen egg lysosome (HEL)-specific RD2-deficient GFP B cells and wild type RFP B cells (with the ratio 1:1) were transferred together with non-fluorescent ovalbumin (OVA)-specific T cells into SMARTA hosts, which were then immunized at the footpad with HEL-OVA two days later. On day 5 after immunization, draining popliteal lymph nodes were harvested and subjected for immunofluorescence histology analysis. At this time point, wild-type RFP B cells have started to cluster into tiny GC, whereas RD2-deficient GFP B cells did not form GCs. Moreover, wild-type B cells in the follicular interior were predominantly Bcl6hi, a characteristic of pre-GC B cells, suggesting that they could serve as a source of GC B cells. By contrast, RD2-deficient GFP B cells were primarily extra-follicular, and infrequently observed in the follicle interior. Most importantly, these cells were typically Bcl6lo, demonstrating that RD2 repression function is essential for pre-GC B cell differentiation. BCL6 knockout mice display a lethal inflammatory phenotype due to aberrant T-cell and macrophage activation. In striking contrast, RD2-deficient mice experienced normal healthy lives with no inflammation, and had nearly normal inflammation cytokine production in B cells and macrophages as well as differentiation of Th1,Th2 and Th17 subtypes. Hence the RD2 repression domain is specifically involved in humoral immunity but has minimal participation in the anti-inflammatory functions of BCL6. Instead we observed that the BCL6 zing finger domain plays the key role in anti-inflammatory functions in macrophages, and through ChIP-competition assays show that this is mediated by directly competing with STATs for binding to chemokine genes. These results highlight an essential role of RD2-mediated transcriptional repression in pre-GC B cell development specifically at the early B-cell activation phase. This is different than mice with BCL6 BTB mutations where early activation is normal and the defect occurs later on in the proliferative phase of GCs. The data suggest a surprising development and cellular context-specific biochemical functions of Bcl6 governing each distinct phase of the humoral immune response and inflammation. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.381 ◽

1996 ◽

Vol 183 (2) ◽

pp. 381-391 ◽

Cited By ~ 140

Author(s):

D A Grillot ◽

R Merino ◽

J C Pena ◽

W C Fanslow ◽

F D Finkelman ◽

...

Keyword(s):

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Cell Lineage ◽

Cell Development ◽

B Cell Development ◽

Immunoglobulin M ◽

Protective Mechanism ◽

And Function ◽

Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

Download Full-text

The Earliest Step in B Lineage Differentiation from Common Lymphoid Progenitors Is Critically Dependent upon Interleukin 7

Journal of Experimental Medicine ◽

10.1084/jem.20020784 ◽

2002 ◽

Vol 196 (5) ◽

pp. 705-711 ◽

Cited By ~ 141

Author(s):

Juli P. Miller ◽

David Izon ◽

William DeMuth ◽

Rachel Gerstein ◽

Avinash Bhandoola ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Gamma Chain ◽

Lineage Differentiation ◽

Lymphoid Progenitors ◽

B Lineage

Little is known about the signals that promote early B lineage differentiation from common lymphoid progenitors (CLPs). Using a stromal-free culture system, we show that interleukin (IL)-7 is sufficient to promote the in vitro differentiation of CLPs into B220+ CD19+ B lineage progenitors. Consistent with current models of early B cell development, surface expression of B220 was initiated before CD19 and was accompanied by the loss of T lineage potential. To address whether IL-7 receptor (R) activity is essential for early B lineage development in vivo, we examined the frequencies of CLPs and downstream pre–pro- and pro-B cells in adult mice lacking either the α chain or the common gamma chain (γc) of the IL-7R. The data indicate that although γc−/− mice have normal frequencies of CLPs, both γc−/− and IL-7Rα−/− mice lack detectable numbers of all downstream early B lineage precursors, including pre–pro-B cells. These findings challenge previous notions regarding the point in B cell development affected by the loss of IL-7R signaling and suggest that IL-7 plays a key and requisite role during the earliest phases of B cell development.

Download Full-text

Increased Frequency of Pre–Pro B Cells in the Bone Marrow of New Zealand Black (NZB) Mice: Implications for aDevelopmental Block in B Cell Differentiation

Developmental Immunology ◽

10.1080/1044667021000003961 ◽

2002 ◽

Vol 9 (1) ◽

pp. 35-45 ◽

Cited By ~ 7

Author(s):

Zhe-Xiong Lian ◽

Hiroto Kita ◽

Tomoyuki Okada ◽

Tom Hsu ◽

Leonard D. Shultz ◽

...

Keyword(s):

New Zealand ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Receptor ◽

Cell Development ◽

B Cell Development ◽

B Cell Differentiation ◽

Differentiation Markers ◽

Cell Stage

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor componentIgα(mb-1). Furthermore, levels of expression of theRug2, λ5andIgβ(B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.

Download Full-text

Long noncoding RNAs in B-cell development and activation

Blood ◽

10.1182/blood-2015-11-680843 ◽

2016 ◽

Vol 128 (7) ◽

pp. e10-e19 ◽

Cited By ~ 48

Author(s):

Tiago F. Brazão ◽

Jethro S. Johnson ◽

Jennifer Müller ◽

Andreas Heger ◽

Chris P. Ponting ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Cell Lineage ◽

Noncoding Rnas ◽

Cell Development ◽

B Cell Development ◽

Long Noncoding Rnas ◽

Human B Cells

AbstractLong noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.

Download Full-text

B1 and B2 B cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers

10.1101/2020.04.30.071209 ◽

2020 ◽

Author(s):

Vinay S. Mahajan ◽

Hamid Mattoo ◽

Na Sun ◽

Vinayak Viswanadham ◽

Grace J. Yuen ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Cell Development ◽

Methylation Pattern ◽

B Cell Development ◽

Developmental Expression ◽

B Lineage ◽

Tet Enzymes ◽

Lineage Specific Genes

AbstractWe show that DNA methylation is a layered process in B lymphocytes. An underlying foundational methylome is stably established during B lineage commitment and overlaid with a DNMT3A-maintained dynamic methylome which is sculpted in distinct ways in B1 and B2 B cells during B cell development. An engineered loss of DNMT3A after commitment to the B lineage unmasks a foundational methylome that is shared in both B1 and B2 sub-lineages. The dynamic methylome is comprised of novel enhancers whose methylation state is maintained by DNMT3A but can be modulated in strikingly different ways in B1 and B2 B cells. During B1 B cell development, the dynamic methylome undergoes a prominent programmed demethylation event that is not observed during B2 B cell development. The methylation pattern of the dynamic methylome is determined by the coincident recruitment of DNMT3A and TET enzymes and it regulates the developmental expression of B1 and B2 lineage-specific genes.

Download Full-text