Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells

Li, LiQi; Jothi, Raja; Cui, Kairong; Lee, Jan Y.; Cohen, T.; Gorivodsky, Marat; Tzchori, Itai; Zhao, Yangu; Hayes, Sandra M.; Bresnick, Emery H.; Zhao, Keji; Westphal, Heiner; Love, Paul E.

doi:10.1038/ni.1978

Cited by 96 publications

(103 citation statements)

References 45 publications

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“…48 a similar function was suggested for LDB1 in intestinal crypts 49 and for LDB1, 50 and LHX2, 51 in hematopoiesis. specifically, in hematopoiesis, LDB1 has a critical role in the maintenance of fetal and adult hematopoietic stem cells and of cells downstream of them in the erythroid lineage.…”

Section: Modularity Of Chip/ldb Transcription Complexes Regulates Celmentioning

confidence: 82%

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

Bronstein

Segal

2011

Fly

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Section: Modularity Of Chip/ldb Transcription Complexes Regulates Celmentioning

confidence: 82%

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

Bronstein

Segal

2011

Fly

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“…In addition to binding sites containing GATA-E-box composite elements, like the +9.5 site, TAL1 occupies GATA motif-containing sites lacking a consensus E-box, presumably via recruitment by the GATA factor (28). The LIM domain binding-1 coregulator LDB1 promotes chromatin looping (39,40) and facilitates HSC maintenance, primitive hematopoietic progenitor generation, and erythroid differentiation (37,(41)(42)(43)(44). Certain patients with MonoMAC who lack GATA2 coding region mutations harbored deletion or point mutations in Fig.…”

Section: Significancementioning

confidence: 99%

“…The E-box binding protein TAL1 cooperates with GATA factors in the assembly of a multicomponent complex on E-box-GATA composite elements at genes important for blood cell development and function (27)(28)(29)(30)(31)(32)(33). The TAL1-interacting proteins LDB1 and LMO2 control the development and function of HSPCs (22,(34)(35)(36)(37)(38). In addition to binding sites containing GATA-E-box composite elements, like the +9.5 site, TAL1 occupies GATA motif-containing sites lacking a consensus E-box, presumably via recruitment by the GATA factor (28).…”

Section: Significancementioning

confidence: 99%

“…The WGATAR motifs and intervening sequence that were removed by homologous recombination are indicated. (B) ChIPsequencing profiles for factor occupancy and histone modifications at the Gata2 locus mined from existing datasets (37,(69)(70)(71)(72). BM, bone marrow; H3K27a, acetylation of H3 at lysine 27; H3K4m1, monomethylation of histone H3 at lysine 4; MEL, murine erythroleukemia cells.…”

Section: Significancementioning

confidence: 99%

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Mechanism governing a stem cell-generating cis -regulatory element

Sanalkumar

Johnson

Gào

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The unremitting demand to replenish differentiated cells in tissues requires efficient mechanisms to generate and regulate stem and progenitor cells. Although master regulatory transcription factors, including GATA binding protein-2 (GATA-2), have crucial roles in these mechanisms, how such factors are controlled in developmentally dynamic systems is poorly understood. Previously, we described five dispersed Gata2 locus sequences, termed the −77, −3.9, −2.8, −1.8, and +9.5 GATA switch sites, which contain evolutionarily conserved GATA motifs occupied by GATA-2 and GATA-1 in hematopoietic precursors and erythroid cells, respectively. Despite common attributes of transcriptional enhancers, targeted deletions of the −2.8, −1.8, and +9.5 sites revealed distinct and unpredictable contributions to Gata2 expression and hematopoiesis. Herein, we describe the targeted deletion of the −3.9 site and mechanistically compare the −3.9 site with other GATA switch sites. The −3.9 −/− mice were viable and exhibited normal Gata2 expression and steady-state hematopoiesis in the embryo and adult. We established a Gata2 repression/reactivation assay, which revealed unique +9.5 site activity to mediate GATA factor-dependent chromatin structural transitions. Loss-of-function analyses provided evidence for a mechanism in which a mediator of long-range transcriptional control [LIM domain binding 1 (LDB1)] and a chromatin remodeler [Brahma related gene 1 (BRG1)] synergize through the +9.5 site, conferring expression of GATA-2, which is known to promote the genesis and survival of hematopoietic stem cells.cis element | HSCs W hereas proximal promoter sequences assemble the basal transcriptional machinery and RNA polymerase, distant cis-regulatory elements often confer tissue-specific or contextdependent transcriptional regulation. Enhancer elements reside many kilobases upstream or downstream of a promoter or within introns, and extensive efforts have focused on elucidating "action-at-a-distance" mechanisms (1). Long-range transcriptional control involves physical interactions between proteins bound at distal regions and promoter sequences and higher order structural transitions, including subnuclear relocalization of target loci (2-4). Given the high frequency of long-range mechanisms at mammalian loci and the mutations that disrupt the function of such elements in pathological conditions, elucidating the underlying mechanisms in development,

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“…5,6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8,9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs.…”

mentioning

confidence: 99%

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.M ore than 70% of recurring chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) involve transcription factors that are master regulators of cell fate. These oncogenic transcription factors determine the gene signature and leukemic cell types (1). Whether these DNA-bound factors may have additional roles beyond modulating gene expression remains unknown. LMO2, a 17-kDa protein defined by tandem zinc finger domains, is an essential nucleation factor that assembles a multipartite transcriptional regulatory complex on gene regulatory regions via direct interaction with the TAL1/SCL transcription factor, LDB1, and other DNA binding transcription factors (2-4, reviewed in refs. 5, 6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8, 9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs. 5, 6). Interestingly, Lmo2 down-regulation is required for terminal erythroid differentiation (11,12). Because commitment to terminal differentiation is coordinated with growth arrest (13), Lmo2 may have additional molecular functions that impede this critical step marked by growth cessation.In mouse models of T-ALL, LMO1 or LMO2 collaborates with SCL to inhibit the activity of two basic helix-loop-helix (bHLH) transcription factors that control thymocyte differentiation, E2A/ TCF3 and HEB/TCF12, causing differentiation arrest (reviewed in ref. 14). However, this inhibition is not sufficient, per se, for leukemogenesis, because both TAL1 and LYL1 inhibit E proteins but require interaction with LMO1/2 to activate the transcription of a self-renewal gene network in thymocytes (15,16) and to induc...

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Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells

Cited by 96 publications

References 45 publications

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

Mechanism governing a stem cell-generating cis -regulatory element

The LMO2 oncogene regulates DNA replication in hematopoietic cells

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