Tài liệu Báo cáo khoa học: Mixed lineage leukemia: roles in gene expression, hormone signaling and

MINIREVIEW

Mixed lineage leukemia: roles in gene expression, hormone

signaling and mRNA processing

Khairul I. Ansari and Subhrangsu S. Mandal

Department of Chemistry and Biochemistry, The University of Texas at Arlington, TX, USA

Introduction

In eukaryotes, gene regulation is a complex process [1].

In addition to RNA polymerase II (RNAPII), there are

numerous other transcription factors and regulatory

proteins that coordinate with RNAPII to accurately

express a particular gene under a specific cellular envi￾ronment. In higher organisms, DNA is complexed with

various histones and other nuclear proteins in the form

of compact chromatins. These chromatins are not easily

accessible to gene expression machinery unless they are

modified or remodeled [1]. Intense research over the

past two decades has led to the discovery of various

chromatin-remodeling factors and histone-modifying

enzymes that modulate chromatin structures to facilitate

gene expression [1]. Histone methyltransferases (HMTs)

are key enzymes that introduce methyl groups into the

lysine side chain of histone proteins and regulate gene

activation and silencing (Fig. 1). Histone H3 lysine 4

(H3K4) methylation is an evolutionarily conserved

mark with fundamental roles in gene activation [2]. Set1

is the only H3K4-specific HMT present in yeast and is a

component of a multiprotein complex called COM￾PASS [3]. In higher eukaryotes, H3K4-specific HMTs

are diverged with increased structural and functional

complexity [4]. In humans, there are at least eight

H3K4-specific HMTs that include mixed lineage leuke￾mia 1 (MLL1), MLL2, MLL3, MLL4, MLL5, hSet1A,

Keywords

epigenetics; estrogen receptor; gene

expression; histone methyltransferase;

hormone signaling; mixed lineage leukemia;

mRNA processing; NR-box; nuclear

receptor; SET domain

Correspondence

S. S. Mandal, Gene Regulation and Disease

Research Laboratory, Department of

Chemistry and Biochemistry, The University

of Texas at Arlington, Arlington, TX 76019,

USA

Fax: +1 817 272 3808

Tel: +1 817 272 3804

E-mail: [email protected]

(Received 14 November 2009, revised 16

January 2010, accepted 28 January 2010)

doi:10.1111/j.1742-4658.2010.07606.x

Mixed lineage leukemias (MLLs) are an evolutionarily conserved trithorax

family of human genes that play critical roles in HOX gene regulation and

embryonic development. MLL1 is well known to be rearranged in myeloid

and lymphoid leukemias in children and adults. There are several MLL

family proteins such as MLL1, MLL2, MLL3, MLL4, MLL5, Set1A and

Set1B, and each possesses histone H3 lysine 4 (H3K4)-specific methyltrans￾ferase activity and has critical roles in gene activation and epigenetics.

Although MLLs are recognized as major regulators of gene activation,

their mechanism of action, target genes and the distinct functions of differ￾ent MLLs remain elusive. Recent studies demonstrate that besides H3K4

methylation and HOX gene regulation, MLLs have much wider roles in

gene activation and regulate diverse other genes. Interestingly, several

MLLs interact with nuclear receptors and have critical roles in steroid￾hormone-mediated gene activation and signaling. In this minireview, we

summarize recent advances in understanding the roles of MLLs in gene

regulation and hormone signaling and highlight their potential roles in

mRNA processing.

Abbreviations

ASCOM, activating signal cointegrator-2 (ASC2) complex; CBP, CREB-binding domain; CGBP, CpG-binding protein; ER, estrogen receptor;

H3K4, histone H3 lysine 4; HMT, histone methyltransferase; HSC, hematopoietic stem cell; LXR, liver X receptor; MLL, mixed lineage

leukemia; NR, nuclear receptor; RAR, retinoic acid receptor; RNAPII, RNA polymerase II; SF, splicing factor.

1790 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS