Xianjiang Lan
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Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β‐Thalassemia Open
β‐thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although …
View article: Dual function of DOT1L suppresses tumor intrinsic immunogenicity in hepatocellular carcinoma
Dual function of DOT1L suppresses tumor intrinsic immunogenicity in hepatocellular carcinoma Open
Immune checkpoint inhibitor (ICB) therapy for many cancers remains limited in patients’ overall response rate. Discovery and development of more effective combinatorial approaches is urgent. Here, through CRISPR/Cas9 genetic screens, we id…
View article: SWI/SNF complex-mediated ZNF410 cooperative binding maintains chromatin accessibility and enhancer activity
SWI/SNF complex-mediated ZNF410 cooperative binding maintains chromatin accessibility and enhancer activity Open
The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic…
Mechanistic dissection of the <i>CHD4</i> enhancers reveals cooperative functions among the homotypic ZNF410 clustered motifs Open
SUMMARY Transcription factors often regulate numerous target genes. However, ZNF410 controls only a single gene, CHD4, in human erythroid cells by its highly restricted chromatin occupancy to the CHD4 locus via two clusters of ZNF410 bindi…
Molecular basis of polycomb group protein-mediated fetal hemoglobin repression Open
The fetal (HbF)-to-adult (HbA) hemoglobin switch is a paradigm for developmental gene expression control with relevance to sickle cell disease and b-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhib…
Allosteric autoregulation of DNA binding via a DNA-mimicking protein domain: a biophysical study of ZNF410–DNA interaction using small angle X-ray scattering Open
ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (…
HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation Open
Increasing fetal hemoglobin (HbF) provides clinical benefit in patients with sickle cell disease (SCD). We recently identified heme-regulated inhibitor (HRI, EIF2AK1), as a novel HbF regulator. Because HRI is an erythroid-specific protein …
View article: ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression
ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression Open
Summary Metazoan transcription factors typically regulate large numbers of genes. Here we identify via a CRISPR-Cas9 genetic screen ZNF410, a pentadactyl DNA binding protein that in human erythroid cells directly and measurably activates o…
The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression Open
Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kin…
The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells Open
Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and β-thalassemia. To identify new HbF regulators that might be amenable to pharmacologic control, we screened a protein domain–focused CRISPR-Cas…
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells Open
A CRISPR screen for RBC regulators Hemoglobin in red blood cells (RBCs) carries oxygen to the tissues. Sickle cell disease is an inherited condition that involves abnormal hemoglobin. Current treatments entail modulating the level of fetal…
USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B Open
Decreased expression of the USP44 deubiquitinase has been associated with global increases in H2Bub1 levels during mouse embryonic stem cell (mESC) differentiation. However, whether USP44 directly deubiquitinates histone H2B or how its act…
Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module Open
The SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary f…